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Xiaojing Wang, Haifeng Liu, Dongjie Zhai, Yanan Qin, Chuifeng Fan, Di Zhang Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences of China Medical University, Shenyang, 110001, People’s Republic of ChinaCorrespondence: Di Zhang; Chuifeng Fan Email zhangdi_new@hotmail.com; cffan@cmu.edu.cnAbstract: Multiple primary lung cancer (MPLC) is considered relatively rare. This report presents an unusual case of multiple pulmonary nodules in a 74-year-old man who presented with three independent synchronous tumors in the right upper lobe. The tumors were diagnosed as peripheral squamous cell carcinoma (SCC), adenocarcinoma, and pulmonary mixed squamous cell and glandular papilloma (mixed papilloma). Mixed papilloma is an extremely rare, benign pulmonary tumor with a typical papillary appearance, showing squamous and glandular epithelial differentiation. The histological and immunohistochemical features of each tumor were analyzed. In addition, molecular pathological examination for epidermal growth factor receptor (EGFR) showed no mutation in two primary cancers. Mixed papilloma showed no BRAF V600E mutation or HPV infection. The present case report provides a clinicopathological understanding of an instance in which three tumors of different pathological types are present in the same lung lobe. Furthermore, it provides a literature review regarding multiple lung nodules, focusing on the clinicopathological diagnosis, clinical treatment, and prognostic assessment of these nodules. This is the first case report of mixed papilloma arising in MPLC.Keywords: multiple primary lung cancer, mixed squamous cell and glandular papilloma, squamous, adenocarcinoma, multiple lung nodules

Xiangyun Wang,* Ping Chen* Department of Otorhinolaryngology, Dongying People’s Hospital, Dongying, Shandong, 257091, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiangyun WangDepartment of Otorhinolaryngology, Dongying People’s Hospital, No. 317 Nanyi Road, Dongying, Shandong, 257091, People’s Republic of ChinaTel/Fax + 86-0546-8901191, Email xiangyunw326@163.comBackground: Many microRNAs (miRNAs) are involved in the progression of nasopharyngeal carcinoma (NPC). This study aimed to examine the expression and clinical significance of microRNA (miR)-362-3p in NPC, especially in Epstein–Barr virus (EBV)-positive patients, and explore its potential mechanism in NPC progression.Methods: miR-362-3p levels and Jumonji C domain 2A (JMJD2A) mRNA levels were detected by quantitative real-time PCR. The diagnostic value of miR-362-3p to distinguish NPC patients and EBV-positive cases was evaluated using receiver operating characteristic analysis. The association of miR-362-3p with NPC survival was assessed by Kaplan–Meier curves and Cox regression analysis. NPC cell proliferation, migration and invasion were determined using Cell Counting Kit-8 and Transwell assays, respectively. A luciferase reporter assay was used to confirm the interaction between miR-362-3p and JMJD2A.Results: miR-362-3p expression was decreased in the serum and tissues of NPC patients and had diagnostic value for screening NPC. According to the survival follow-up, NPC survivors had significantly higher miR-362-3p, and miR-326-3p was demonstrated as an independent prognostic indicator of NPC. Interestingly, it is found that EBV-positive NPC patients and cells had significantly lower miR-362-3p compared with EBV-negative NPC patients and cells and had certain ability to distinguish EBV-positive patients. Moreover, miR-362-3p inhibited the proliferation, migration and invasion of both EBV-positive and -negative NPC cells, and these effects might be mediated by targeting JMJD2A.Conclusion: Abnormal miR-362-3p expression is related to EBV-infection and prognosis in NPC patients and may be involved in NPC progression by targeting JMJD2A.Keywords: microRNAs, Epstein–Barr virus, prognosis, nasopharyngeal carcinoma, tumor progression, diagnosis

Qiang Yin, Peng Li, Peng Wang, Zhen Zhang, Qun Liu, Zengfeng Sun, Wenliang Li, Li Ma, Xiaoguang Wang Department of Neurosurgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060, People’s Republic of ChinaCorrespondence: Xiaoguang Wang; Li Ma Tel +86 22 2334 0123 2061; +86 22 2334 0123 2062Fax +86 22 2335 9337Email tchwangxg@163.com; LMa7@tmu.edu.cnPurpose: The performance of alectinib and crizotinib in untreated anaplastic lymphoma kinase (ALK)-positive patients with non-small-cell lung cancer (NSCLC) and symptomatic and synchronic brain metastases is largely unknown. This retrospective study assessed the effectiveness of alectinib and crizotinib, together with intracranial therapies in a cohort of these patients.Patients and Methods: This study included 34 previously untreated ALK-positive NSCLC patients with three or fewer intracranial metastases. Of these patients, 13 received oral alectinib 600 mg twice daily, and 21 received oral crizotinib 250 mg twice daily, until progressive disease, unacceptable toxicity, or death. All intracranial metastases were treated with craniotomy, CyberKnife, or both.Results: Median overall progression-free survival (PFS) was 32.8 months (95% CI 24.4– 41.2 months) in patients treated with alectinib and 8.0 months (95% CI 7.3– 8.7 months) in patients treated with crizotinib. Median PFS of brain lesions was not yet reached with alectinib (95% CI 30.1 months–not estimated) and was 8.5 months (95% CI 7.2– 12.3 months) with crizotinib. Median PFS of lung lesions was 38.5 months (95% CI 27.5– 49.5 months) with alectinib and 9.2 months (95% CI 7.4– 11.0 months) with crizotinib. Median overall survival was not yet reached with alectinib (95% CI 31.0 months–not estimated) and 30.3 months (95% CI 27.3– 37.1 months) with crizotinib.Conclusion: Compared with crizotinib, alectinib showed superior efficacy and lower toxicity in the treatment of ALK-positive patients with NSCLC and symptomatic and synchronic brain metastases. The inclusion of intracranial therapies such as craniotomy or CyberKnife further improved the brain PFS and overall survival of these patients.Keywords: alectinib, crizotinib, non-small-cell lung cancer, brain metastasis, intracranial therapies

Xi Wang, Jinping Wang, Xue Luo, Jinxi Lu, Liang Wang, Qingchang Li, En-Hua Wang Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, 110001, People’s Republic of ChinaCorrespondence: Liang WangDepartment of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, 110001, People’s Republic of ChinaTel/Fax +86 24 23261638Email cmuwangliang@qq.comAbstract: Nuclear protein in testis (NUT) carcinoma (NC) is a poorly differentiated malignant tumor with a poor prognosis, which is caused by the NUTM1 gene rearrangement. Positive staining of NUT using immunohistochemistry (IHC) or gene rearrangement of NUTM1 revealed by genetic analysis, such as fluorescence in situ hybridization (FISH) or next-generation sequencing (NGS), are important strategies used for accurate diagnosis. In the current study, we present a case of NC in an 18-year-old man who had a chief complaint of nasal congestion, nasal bleeding, and anosmia. Magnetic resonance imaging revealed a mass in the nasal cavity and nasal septum. The initial pathological diagnosis was basaloid squamous cell carcinoma. Based on the tumor location and abrupt keratinization, further genetic tests were performed, and NC was diagnosed using FISH, which was further verified by IHC. However, neither DNA-based NGS nor RNA-based NGS revealed the NUTM1 gene rearrangement. Using this case as a basis, we have reviewed the related literature, compared the common diagnostic methods of NC, and discussed the advantages and limitations of current tools employed for molecular analysis of the gene fusion.Keywords: NUTM1, NUT midline carcinoma, FISH, next-generation sequencing, gene rearrangement

Xia Wang,1,* Long Huang,1,* Jing Cai,1 Anwen Liu1,2 1Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330000, Jiangxi Province, People’s Republic of China; 2Jiangxi Key Laboratory of Clinical Translational Cancer Research, Nanchang, 330000, Jiangxi Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Anwen LiuDepartment of Oncology, The Second Affiliated Hospital of Nanchang University, No. 1, Minde Street, Nanchang, Jiangxi Province, 330000, People’s Republic of ChinaEmail awliu666@163.comAbstract: Epidermal growth factor receptor (EGFR) fusions are rare genomic events in non-small-cell lung cancer (NSCLC). With advances in detection technology, some uncommon genomic mutation events, including EGFR fusions, have been detected. There are no standard treatment options for NSCLC patients harboring EGFR fusion. Herein, we report a case of KIF5B-EGFR fusion in NSCLC responding to tyrosine kinase inhibitors (TKIs). A 50-year-old male underwent left upper lobectomy followed by adjuvant chemotherapy for pathological stage IA3 lung adenocarcinoma. The tumor tissue was subjected to next-generation sequencing (NGS) and showed a KIF5B-EGFR fusion. When cancer recurrence occurred thirteen months later, the patient received afatinib (40 mg qd) as second-line treatment, and a partial response was observed, which resulted in an 11-month progression-free survival (PFS). This case provides valuable information on the response to afatinib in an NSCLC patient with a novel KIF5B-EGFR fusion. The NGS assay provides a powerful tool for identifying rare or atypical EGFR gene mutations in patients with NSCLC, which should be encouraged in clinical practice.Keywords: KIF5B-EGFR, EGFR fusion, next-generation sequencing, afatinib, non-small cell lung cancer

Xi Wang, Zhe Cheng, Lingling Dai, Tianci Jiang, Pengfei Li, Liuqun Jia, Xiaogang Jing, Lin An, Meng Liu, Shujun Wu, Yu Wang Department of Respiration, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, People’s Republic of ChinaCorrespondence: Zhe ChengDepartment of Respiration, The First Affiliated Hospital of Zhengzhou University, Jianshe East Road No. 1, Zhengzhou, 450052, Henan, People’s Republic of ChinaEmail chengzhezzu@outlook.comBackground: Long non-coding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) plays a crucial role in non-small cell lung cancer (NSCLC). Nonetheless, regulatory effects of PVT1 on functions of NSCLC cells remain blurry.Methods: Relative expression levels of PVT1, miR-551b and FGFR1 mRNA in tumor tissues and cells were examined employing quantitative real-time polymerase chain reaction (qRT-PCR); CCK-8 and BrdU assays were utilized for measuring cell viability and proliferation of H1299 and A549 cells; cell migration and invasion were detected deploying Transwell assay; dual-luciferase assay was used for the validation of binding sequence between PVT1 and miR-551b. FGFR1 expression in protein level was quantified employing Western blot.Results: PVT1 was highly expressed in NSCLC tissues and cell lines, whereas miR-551b expression was down-regulated. Overexpression of PVT1 potentiated viability, proliferation, migration and invasion of NSCLC cells while miR-551b inhibited the biological behaviors mentioned above. MiR-551b was predicted and then confirmed as a direct downstream target of PVT1. Meanwhile, a negative correlation was observed between PVT1 expression and miR-551b expression in NSCLC tissues. Besides, PVT1 could increase FGFR1 expression by repressing miR-551b expression.Conclusion: PVT1 promotes the proliferation, migration and invasion of NSCLC cells by indirectly mediating FGFR1 via targeting miR-551b.Keywords: lncRNA PVT, miR-551b, FGFR1, NSCLC

Feng Cheng,1,* Jintao Dou,1,2,* Yong Zhang,1,3,* Xiang Wang,1,4,* Huijun Wei,5 Zhijian Zhang,1,5 Yuxiang Cao,4,6 Zhihao Wu1,5,7,8 1Research Laboratory of Tumor Microenvironment, Wannan Medical College, Wuhu, 241001, People’s Republic of China; 2School of Anesthesiology, Wannan Medical College, Wuhu, 241001, People’s Republic of China; 3School of Clinical Medicine, Wannan Medical College, Wuhu, 241001, People’s Republic of China; 4School of Laboratory Medicine, Wannan Medical College, Wuhu, 241001, People’s Republic of China; 5School of Preclinical Medicine, Wannan Medical College, Wuhu, 241001, People’s Republic of China; 6Provincial Engineering Laboratory for Screening and Re-Evaluation of Active Compounds of Herbal Medicines in Southern Anhui, Wannan Medical College, Wuhu, 241001, People’s Republic of China; 7Anhui Province Key Laboratory of Active Biological Macro-Molecules Research, Wannan Medical College, Wuhu, 241001, People’s Republic of China; 8Key Laboratory of Non-Coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, 241001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhihao WuResearch Laboratory of Tumor Microenvironment, Wannan Medical College, Wuhu, 241001, People’s Republic of ChinaEmail zwu2ster@wnmc.edu.cnPurpose: The epithelial-to-mesenchymal transition (EMT) is a fundamental process in tumor progression that endows cancer cells with migratory and invasive potential. Snail, a zinc finger transcriptional repressor, plays an important role in the induction of EMT by directly repressing the key epithelial marker E-cadherin. Here, we assessed the effect of urolithin A, a major metabolite from pomegranate ellagitannins, on Snail expression and EMT process.Methods: The role of Snail in urolithin A-induced EMT inhibition in lung cancer cells was explored by wound healing assay and cell invasion assay. The qRT-PCR and CHX assay were performed to investigate how urolithin A regulates Snail expression. Immunoprecipitation assays were established to determine the effects of urolithin A in mdm2-Snail interaction. In addition, the expression of p53 was manipulated to explore its effect on the expression of mdm2 and Snail.Results: The urolithin A dose-dependently upregulated epithelial marker and decreased mesenchymal markers in lung cancer cells. In addition, exposure to urolithin A decreased cell migratory and invasive capacity. We have further demonstrated that urolithin A inhibits lung cancer cell EMT by decreasing Snail protein expression and activity. Mechanistically, urolithin A disrupts the interaction of p53 and mdm2 which leads Snail ubiquitination and degradation.Conclusion: We conclude that urolithin A could inhibit EMT process by controlling mainly Snail expression. These results highlighted the role of pomegranate in regulation of EMT program in lung cancer.Keywords: urolithin A, ellagitannin metabolite, epithelial–mesenchymal transition, Snail, mdm2, lung cancer

Chunxiang Li,1 Hengchang Liu,2 Ran Wei,2 Zheng Liu,2 Haipeng Chen,2 Xu Guan,2 Zhixun Zhao,2 Xishan Wang,2 Zheng Jiang2 1Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 2Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Zheng JiangDepartment of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Chaoyang District, Beijing, People’s Republic of ChinaTel +86 10-87787110Email zr7780@163.comBackground/Aims: Long non-coding ribonucleic acids (lncRNAs) are involved in the progression of cancers and affect the response to radiation therapy. This study was to investigate the mechanism of lncRNA EGOT in the radiosensitivity of rectal cancer.Methods: The mRNA expression of EGOT, miR-211-5p and ErbB4 in rectal cancer tissues and cells was detected by qRT-PCR. The protein expression of ErbB4 was detected by Western blot. Dual-luciferase reporter assay and ribonucleic acid immunoprecipitation (RIP) were used to confirm the interaction between EGOT and miR-211-5p or miR-211-5p and ErbB4. Transfection technology was used to down-regulate and up-regulate the expression of EGOT and miR-211-5p in rectal cancer cells, respectively. MTT, colony formation and flow cytometry were used to detect the effect of EGOT and miR-211-5p on proliferation, invasion, migration and apoptosis of rectal cancer cells.Results: The expression of EGOT was up-regulated in rectal cancer tissues and cells, and the expression of EGOT was related to the late stage of pathology. EGOT knockdown inhibited the proliferation and colony formation of rectal cancer cells and induced the apoptosis of rectal cancer cells. Moreover, EGOT knockdown was significantly enhanced the effects of radiotherapy on rectal cancer in vivo and in vitro. Furthermore, EGOT was found to serve as a sponge of miR-211-5p, and ErbB4 was a downstream target of miR-211-5p. EGOT enhanced the expression of ErbB4 by regulating miR-211-5p. MiR-211-5p inhibitor restored the effect of EGOT knockdown on the radiosensitivity of rectal cancer.Conclusion: Down-regulation of EGOT could inhibit the growth of rectal cancer cells by regulating the miR-211-5p/ErbB4 axis and improve the radiosensitivity of rectal cancer cells. EGOT may be a new therapeutic target for rectal cancer.Keywords: EGOT, miR-211-5p, ErbB4, rectal cancer, radiosensitivity

Xue Wang,1 Yan Guo,2 Chunyu Wang,3 Qiang Wang,2 Guangqi Yan4 1Department of Orthodontics, School of Stomatology, China Medical University, Shengyang, Liaoning, 110002, People’s Republic of China; 2Department of Central Laboratory, School of Stomatology, China Medical University, Shengyang, Liaoning, 110002, People’s Republic of China; 3Department of Cell Biology, Key Laboratory of Cell Biology, and Key Laboratory of Medical Cell Biology, School of Life Sciences, China Medical University, Shengyang, Liaoning, 110002, People’s Republic of China; 4Department of Oral and Maxillofacial Surgery, School of Stomatology, China Medical University, Shengyang, Liaoning, 110002, People’s Republic of ChinaCorrespondence: Guangqi YanDepartment of Oral and Maxillofacial Surgery, School of Stomatology, China Medical University, NO. 117, Nanjingbei Street, Shenyang, Liaoning, 110002, People’s Republic of ChinaEmail yanguangqi_1982@163.comBackground: Long non-coding RNAs (lncRNAs) are implicated in cancer-related biological processes such as cell proliferation, cell cycle progression, cell migration, cell invasion, and chemoresistance. However, the effects of the lncRNA ZEB1-AS1 on oral squamous cell carcinoma (OSCC) have not been adequately demonstrated. The aims of our current study were to explore the roles of lncRNA ZEB1-AS1 in OSCC progression to reveal the potential mechanism.Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure relative ZEB1-AS1 expression levels in OSCC tissues and adjacent non-cancerous tissues. The biological functions of ZEB1-AS1 in OSCC growth and progression were identified by cell proliferation, wound healing, and in vitro transwell assays as well as in vivo xenograft model. The underlying mechanism was detected with a dual-luciferase reporter (DLR) assay.Results: The up-regulation of ZEB1-AS1 and downregulation of miR-23a-3p (miR-23a) were found in OSCC cancer tissues. A ZEB1-AS1 knockdown remarkably suppressed in vitro cancerous, biological processes of OSCC cell lines such as cell proliferation, invasion, migration, and epithelial–mesenchymal transition (EMT). The tumor growth was also inhibited by silencing ZEB1-AS1 in vivo, and a DLR assay confirmed the association between ZEB1-AS1 and miR-23a.Conclusion: The newly identified lncRNA ZEB1-AS1 functions as a tumor promoter in OSCC through regulation of miR-23a. Based on these results, ZEB1-AS1 could be a valid molecular target for treating oral cancer.Keywords: OSCC, lncRNA ZEB1-AS1, miR-23a, EMT

Zhiqin Lu,1 Xia Wang,1,2 Yuxi Luo,1 Jianping Wei,1 Zhimin Zeng,1,2 Qiang Xiong,1,2 Jing Cai,1,2 Anwen Liu1,2 1Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China; 2Jiangxi Key Laboratory of Clinical Translational Cancer Research, Nanchang, Jiangxi Province, People’s Republic of ChinaCorrespondence: Jing Cai; Anwen LiuDepartment of Oncology, The Second Affiliated Hospital of Nanchang University, No. 1, Minde Street, Nanchang, Jiangxi Province, 360000, People’s Republic of ChinaTel +8615270905381; Tel +8615270905381Email cjdl879@163.com; awliu666@163.comAbstract: Leptomeningeal metastasis (LM) is a disastrous complication of advanced lung adenocarcinoma (LAC) associated with poor prognosis and rapid deterioration of performance status. The prevalence of epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) co-alterations in patients with LAC was low. Herein, we report a patient with alterations in both EGFR (p. G719A+L747V) and echinoderm microtubule-associated protein-like ALK (EML4-ALK) fusion and LM who was treated with afatinib. The patient’s clinical symptoms improved, and imaging examination revealed reduced intracranial and extracranial lesions. The progression-free survival (PFS) using afatinib for LM was 25 months, and no severe adverse events occurred.Keywords: afatinib, leptomeningeal metastasis, EGFR, ALK, co-alterations, lung adenocarcinoma

Yunfei Ma,1 Guangda Li,2 Mingwei Yu,1 Kexin Cao,1 Qiwei Li,1 Xu Sun,3 Guowang Yang,1 Xiaomin Wang1 1Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, People’s Republic of China; 2School of Graduates, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 3Department of Integrated Chinese and Western Medicine, The Tumor Hospital Affiliated to Zhengzhou University, Zhengzhou, People’s Republic of ChinaCorrespondence: Xiaomin Wang; Guowang YangBeijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, People’s Republic of ChinaTel/Fax +86 10-52176508; +86 10-52177301Email wangxiaomin_bhtcm@126.com; yangguowang_bhtcm@126.comObjective: To systematically explore the pharmacological mechanism of Radix Paeoniae Rubra (RPR) against lung cancer (LC).Methods: A network pharmacology approach, which involves active ingredients and target forecast, network construction, gene ontology and pathway enrichment, was employed in this research. In addition, the effect of Baicalein (BAI) in RPR on A549 cells was researched in vitro and in vivo.Results: A total of 159 targets of the 29 active components in RPR were procured by pharmacokinetic parameters. The network analysis showed that β-sitosterol, baicalein, (+)-catechin, ellagic acid, stigmasterol, (2R, 3R)-4-methoxyl-distylin were the main ingredients and JUN, VEGFA, BCL2 were the hub targets of RPR in the treatment of LC. The functional enrichment analysis showed that RPR likely was useful to LC by regulating numerous pathways including Pathways in cancer, MAPK signaling pathway and so on. MTT results showed that 100μM, 200μM, 400μM of BAI had a time and dose-dependent inhibitory effect on A549 cells proliferation; Wound healing and transwell assays showed that 100μM, 200μM, 400μM of BAI could significantly restrain the migration and invasion of A549 cells; Flow cytometry assay results showed that 100μM, 200μM, 400μM of BAI could induce apoptosis of A549 cells. In vivo, BAI (50, 100 mg/kg) significantly inhibited tumor growth and promoted apoptosis of tumor cells compared with the control group.Conclusion: BAI in RPR may exert anti-tumor effects by inhibiting the proliferation, migration and invasion of LC cells, and inducing the apoptosis of LC cells.Keywords: network pharmacology, radix paeoniae rubra, lung neoplasms, baicalein

Ming Zhang,* Xiaoyu Wang,* Zhenghua Wang Department of Gastrointestinal Oncology (Ward I), The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 121000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhenghua WangDepartment of Gastrointestinal Oncology (Ward I), The First Affiliated Hospital of Jinzhou Medical University, No. 2, Section 5, Renmin Street, Jinzhou, Liaoning, 121000, People’s Republic of ChinaEmail wangzhenghua1977@163.comObjective: To study the correlation between tumor abnormal protein (TAP) and tumor markers, blood glucose, uric acid and coagulation function in gastric adenocarcinoma and to evaluate the clinical application of TAP in the diagnosis of gastric adenocarcinoma.Methods: A total of 34 nontumor patients and 95 gastric adenocarcinoma patients admitted to the First Affiliated Hospital of Jinzhou Medical University were enrolled in this study. Fresh blood from patients’ fingertips was collected, all blood samples were examined with TAP testing kit, and then searched and measured the condensed particulate matter.Results: The comparison of TAP between nontumor patients and gastric adenocarcinoma patients was statistically significant (P< 0.05). Bivariate correlation analysis was conducted between TAP and other related tumor markers (alpha-fetoprotein, carcinoembryonic antigen, carbohydrate antigen 19– 9 (CA199), carbohydrate antigen 72– 4 (CA72-4)), blood glucose, uric acid, and coagulation function-related indicators, and the results showed that the correlation between TAP and CA199, CA72-4, and activated partial prothrombin time was statistically significant. In addition, according to the analysis results, there was no significant difference among TAP and age, height and weight in the tumor population and the nontumor population.Conclusion: TAP can be used for the screening and diagnosis of gastric adenocarcinoma, and the effect of TAP combined with other indicators is more significant than TAP alone.Keywords: tumor abnormal protein, gastric adenocarcinoma, tumor markers, blood glucose, uric acid, coagulation function

Xiuli Jin,1 Weixin Fu,2 Dan Li,1 Ningning Wang,1 Jiayu Chen,1 Zilu Zeng,1 Jiaqi Guo,1 Hao Liu,3 Xinping Zhong,3 Hu Peng,4 Xin Yu,5 Jing Sun,1 Xinhe Zhang,1 Xue Wang,1 Beibei Xu,1 Yingbo Lin,6 Jianping Liu,4 Claudia Kutter,7 Yiling Li1 1Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang, 110001, People’s Republic of China; 2Science Experiment Center of China Medical University, Shenyang, 110122, People’s Republic of China; 3Department of Hepatobiliary Surgery, First Affiliated Hospital of China Medical University, Shenyang, 110001, People’s Republic of China; 4Emergency Department, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200072, People’s Republic of China; 5Department of Human Anatomy, School of Basic Medicine, Dali University, Dali, Yunnan, 671003, People’s Republic of China; 6Department of Oncology-Pathology, Karolinska Institute, Stockholm, 17177, Sweden; 7Department of Microbiology, Tumor and Cell Biology, Science for Life Laboratory, Karolinska Institute, Stockholm, 17177, SwedenCorrespondence: Claudia KutterDepartment of Microbiology, Tumor and Cell Biology, Science for Life Laboratory, Karolinska Institute, Stockholm, 17177, SwedenEmail claudia.kutter@ki.seYiling LiDepartment of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang, 110001, People’s Republic of ChinaEmail lyl-72@163.comObjective: As one of the most common neoplastic diseases, hepatocellular carcinoma (HCC) has a high morbidity and mortality, which seriously threatens human health and places a heavy burden on society and medical care. At present, effective early diagnosis, prognosis and treatment of HCC are limited. Altered gene expression patterns of lncRNA are associated with the occurrence, development and prognosis of various malignancies, including HCC. The aim of this study was to investigate the correlation between the expression of LINC01268 and HCC, and to elucidate the potential underlying molecular mechanism.Methods: Expression level and localization of LINC01268 in human liver cancer cells and HCC tissues were investigated using RT-qPCR and fluorescent in situ hybridization (FISH), respectively. Correlation of expression levels of LINC01268 and MAP3K7 with differentiation and poor overall patient survival of HCC were analyzed using in house collected and publicly available HCC tissue data. RT-qPCR and Western blot were applied to inspect the effects of depletion and overexpression of LINC01268 on MAP3K7 expression. HCC cell proliferation and apoptosis were also investigated by simultaneous overexpression of LINC01268 and knockdown of MAP3K7, in order to delineate that MAP3K7 is a downstream effector of LINC01268.Results: In this study, we identified that LINC01268 was highly expressed in HCC cell lines and tissues. High LINC01268 expression level was associated with lower HCC nodule number, moderate/poor differentiation and poor overall survival. Knockdown of LINC01268 inhibited the proliferation of HCC cells, which was enhanced by overexpression of LINC01268. Co-expression analysis implied an interaction between LINC01268 and MAP3K7. Similar to LINC01268, MAP3K7 was highly expressed in HCC cells, and positively correlated with moderate/poor differentiation as well as poor prognosis. Knockdown of LINC01268 in HCC cell lines led to reduction of MAP3K7 at both mRNA and protein levels. Phenotypic effects due to LINC01268 overexpression in HCC cells were reversed by knockdown of MAP3K7.Conclusion: Taken together, the abnormal high expression of LINC01268 is associated with HCC progression via regulating MAP3K7, suggesting LINC01268 as a novel marker for HCC prognosis and potentially a new therapeutic target.Keywords: LINC01268, MAP3K7, hepatocellular carcinoma, proliferation, prognosis

Shishuai Wen,1,2,* Ning Qu,1,2,* Ben Ma,1,2,* Xiao Wang,1,2,* Yi Luo,1,2,* Weibo Xu,1,2 Hongyi Jiang,1,2 Yan Zhang,2,3 Yu Wang,1,2 Qinghai Ji1,2 1Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China; 3Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qinghai Ji; Yu WangDepartment of Head & Neck Surgery, Fudan University Shanghai Cancer Center, No. 270, Dong’an Road, Shanghai, 200032, People’s Republic of ChinaFax +021 6404 0207Email jq_hai@126.com; neck130@sina.comBackground and Objectives: Targeting cancer-associated fibroblast (CAF) is being explored as an approach to improve cancer therapies. The roles of CAF remain unclarified in malignant transformation of papillary thyroid cancer (PTC) into dedifferentiated thyroid cancer (DDTC). This study aimed to investigate correlations of CAF with dedifferentiation and clinicopathological characteristics of thyroid cancer.Materials and Methods: We applied three different mRNA-based CAF gene signatures to quantify CAF in our cohort, the Gene Expression Omnibus (GEO) cohort and The Cancer Genome Atlas (TCGA) cohort, and analyzed expression of α-SMA by immunohistochemistry in thyroid cancer. The CAF score was analyzed for its associations with clinicopathological characteristics, genetic mutations, tumor-associated signaling pathways and immune landscape.Results: The CAF score increased significantly in DDTCs compared with normal thyroid tissues and PTCs, and the α-SMA-positive CAFs were found enriched in DDTCs. The high CAF score showed a significant correlation with the anaplastic phenotype in DDTC and low thyroid differentiation score in PTC. Patients with a high CAF score remarkably increased the risk of aggressive outcomes in both DDTC and PTC. Furthermore, the CAF score was positively correlated with genetic mutations, oncogenic signaling pathways, the immune score and increased expression of tumor microenvironment (TME) target markers.Conclusion: Our findings suggest CAFs positively correlate with dedifferentiation and aggressive outcomes of thyroid cancer, and targeting CAFs as a therapeutic approach may benefit DDTC patients.Keywords: CAF, dedifferentiation, DDTC, PTC

Tianyi Ma,1 Tianyu Qiao,1 Ziming Yuan,1 Guiyu Wang,1 Rui Huang,1 Meng Wang,1 Hanqing Hu,1 Yihao Zhu,1 Xiaoming Zou,2 Xishan Wang1,3 1Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, People’s Republic of China; 2Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, People’s Republic of China; 3Department of Colorectal Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100021, People’s Republic of ChinaCorrespondence: Xiaoming Zou; Xishan Wang Email zou4930@163.com; wxshan1208@126.comBackground: The identification of cancer-associated long noncoding RNAs and the investigation of their molecular and biological functions are important for understanding the molecular biology and progression of cancer. JAKMIP2-AS1 has not been reported in the literature, especially in the context of colorectal cancer. The aim of the present study was to examine the expression pattern of JAKMIP2-AS1 in colorectal cancer (CRC) and evaluate its biological role and clinical significance in tumor progression.Methods: JAKMIP2-AS1 expression was analyzed in 56 CRC tissues and nine CRC cell lines by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Overexpression and RNA interference (RNAi) approaches were used to investigate the biological functions of JAKMIP2-AS1. The effect of JAKMIP2-AS1 on proliferation was evaluated by CCK-8, colony formation, and EdU assays. Subcutaneous injection of cells was used to study proliferation in BALB/c nude male mice. Proliferation-related protein levels were examined by immunohistochemical analysis. Differences between groups were tested for significance using Student’s t-test (two-tailed).Results: JAKMIP2-AS1 was highly expressed in both CRC samples and cell lines compared with the corresponding normal counterparts. The upregulation of JAKMIP2-AS1 expression promoted the proliferation of colorectal cancer cells. Moreover, patients with high levels of JAKMIP2-AS1 expression had a relatively poor prognosis. Inhibition of JAKMIP2-AS1 by RNAi decreased the proliferation of CRC cells in vitro and impeded cell growth in vivo. Ki-67 and PCNA levels were affected by JAKMIP2-AS1 knockdown or overexpression in vivo.Conclusion: Our findings indicate that JAKMIP2-AS1 is significantly upregulated in CRC tissues and regulates CRC cell proliferation. Thus, JAKMIP2-AS1 may represent a new marker of poor prognosis and is a potential therapeutic target for CRC intervention.Keywords: colorectal cancer, long noncoding RNA, proliferation, prognosis

Ziming Yuan,1 Zhixun Zhao,2 Hanqing Hu,1 Yihao Zhu,1 Weiyuan Zhang,1 Qingchao Tang,1 Rui Huang,1 Feng Gao,1 Chaoxia Zou,3 Guiyu Wang,1 Xishan Wang1,2 1Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China; 2Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 3Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, Heilongjiang, People’s Republic of ChinaCorrespondence: Xishan Wang Email wxshan_1208@126.comGuiyu Wang Email guiywang@163.comBackground: The liver is the most frequent site for metastatic spread in colorectal cancer (CRC) patients, and these patients have much poorer prognosis than those without metastasis. Previous studies have shown that IgG Fc binding protein (FCGBP) plays important roles in tumorigenesis, progression, and prognosis, but its role in CRC metastasis remains unclear.Purpose: In this study, we are aimed to explore the significance of FCGBP in liver metastatic CRC (LMCRC) patients.Methods: We analyzed the expression of FCGBP RNA between CRC primary samples and liver metastatic samples in the Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA). Next, we assessed the expression of FCGBP protein in 135 paired primary CRC (PC) samples and LMCRC samples. Finally, we explored the relationship between the expression features and clinicopathological characteristics.Results: The expression data of FCGBP were obtained from the GEO and TCGA databases. FCGBP RNA expression was evaluated between primary lesions (PC) and liver metastatic lesions (LM). FCGBP RNA was down-regulated in PC and LM, and especially lower in LM (p< 0.001). Next, the expression of FCGBP protein was evaluated by an immunohistochemistry array in 135 paired primary tumor tissues and metastatic tissues. We found that FCGBP protein was down-regulated in primary lesions and metastatic lesions, especially in metastatic lesions. According to the immunohistochemistry score (SI), each cohort was divided into FCGBP-positive (SI=4– 12) and FCGBP-negative (SI=0– 3) groups. In both groups, the levels of CEA (PC group, 3.880 vs 77.049, p< 0.001; LM group, 3.890 vs 14.239, p=0.008) and CA19-9 (PC group, 8.610 vs 111.700, p< 0.001; LM group, 7.660 vs 19.380, p=0.037) were lower than those in the FCGBP-negative group. FCGBP positivity in the LM cohort was an independent risk factor in both overall survival (HR 1.573, 95% Cl [1.017– 2.433], p=0.042) and disease-free survival (HR 1.869, 95% Cl [1.256– 2.781], p=0.002).Conclusion: This study found a relationship between FCGBP expression and clinical information of LMCRC patients, and found that FCGBP expression decreased with disease development. The expression of FCGBP in liver metastasis is associated with both the overall and progression-free survival. Our results show that FCGBP could be a promising prognostic factor for LMCRC.Keywords: colorectal cancer, IgG Fc binding protein, liver metastasis, prognosis, biomarker

Yufei Fu,1 Fanfan Zhu,1 Zhongjun Ma,2 Bin Lv,1 Xi Wang,1 Chunyan Dai,1 Xiaoqiong Ma,1 Pei Liu,1 Hang Lv,1 Xin Chen,3 Zhe Chen,1 Li Shen4 1Key Laboratory of Digestive Pathophysiology of Zhejiang Province, Insititute of Cancer Research, First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 2Institute of Marine Biology and Natural Products, Department of Ocean Science and Engineering, Zhejiang University, Hangzhou, People’s Republic of China; 3Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Zhejiang University, Hangzhou, People’s Republic of China; 4Institute of Basic Theory of Chinese Medicine, China Academy of Chinese Medicine Science, Beijing, People’s Republic of ChinaCorrespondence: Li ShenInstitute of Basic Theory of Chinese Medicine, China Academy of Chinese Medicine Science, 16 Nanxiao Street, Dongzhimennei, Dongcheng Distract, Beijing, People’s Republic of ChinaTel +86-18611325278Email shenli1116@126.comZhe ChenKey Laboratory of Digestive Pathophysiology of Zhejiang Province, First Affiliated Hospital, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou 310053, People’s Republic of ChinaTel +86-571-86620280Email chenzhe2007@zcmu.edu.cnBackground: Physalis alkekengi var. franchetii is an herb that possesses various ethnopharmacological applications. Herein, our current study focuses on the antitumor effect of a combination of physalins, which are regarded as the most representative secondary metabolites from calyces of Physalis alkekengi var. franchetii.Materials and Methods: We mainly investigated the antitumor activity of the physalins extracted from Physalis alkekengi var. franchetii on both solid and hematologic cancers. The main cells used in this study were NCI-H1975 and U266 cells. The major assays used were the CCK-8 assay, Western blot analyses, immunofluorescence assay and Annexin V assay, and a xenograft mouse model was used.Results: The results showed that physalins exhibited a strong antitumoural effect on both non-small cell lung cancer (NSCLC) and multiple myeloma (MM) cells by suppressing constitutive STAT3 activity and further inhibiting the downstream target gene expression induced by STAT3 signaling, which resulted in the enhanced apoptosis of tumor cells. Moreover, physalins significantly reduced tumor growth in xenograft models of lung cancer.Conclusion: Collectively, these findings demonstrated that the physalins from Physalis alkekengi var. franchetii may potentially act as cancer preventive or chemotherapeutic agents for NSCLC and MM by inhibiting the STAT3 signaling pathway. The present study served as a promising guide to further explore the precise mechanism of Physalis alkekengi var. franchetii in cancer treatment.Keywords: Physalis, apoptosis, non-small cell lung carcinoma, multiple myeloma, STAT3

Qiaoling Zheng,1,2 Jianyong Zhang,1,3 Xinchen Wang,4 Wenxiong Zhang,1 Yipo Xiao,4 Sheng Hu,1 Jianjun Xu1 1Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province 330006, People’s Republic of China; 2Jiangxi Health Vocational College, Nanchang, Jiangxi 330000, People’s Republic of China; 3The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province 550000, People’s Republic of China; 4Jiangxi Key Laboratory for Mass Spectrometry and Instrumentation, East China University of Technology, Nanchang, Jiangxi Province 330013, People’s Republic of ChinaCorrespondence: Jianjun Xu Tel + 8613907913526Email xujianjun3526@163.comPurpose: Increased use of low-dose spiral computed tomography (LDCT: low-dose computed tomography) screening has contributed to more frequent incidental detection of peripheral lung nodules, part of them were adenocarcinoma, which need to be further evaluated to establish a definitive diagnosis. Here, our primary objective was to evaluate the ambient mass spectrometry (AMS) sputum analysis as a non-invasive lung adenocarcinoma (LAC) diagnosis solution.Patients and Methods: Neutral desorption extractive electrospray ionization mass spectrometry (ND-EESI-MS) and collision induced dissociation (CID) were used to detect sputum metabolites from 143 spontaneous sputum samples. Partial least squares-discriminant analysis (PLS-DA) was used to refine the biomarker panel, whereas orthogonal PLS-DA (OPLS-DA) was used to operationalize the enhanced biomarker panel for diagnosis.Results: In this approach, 19 altered metabolites were detected by ND-EESI-MS from 76 cases of LAC and 67 cases of control. Significance testing and receiver operating characteristic (ROC) analysis identified 5 metabolites [hydroxyphenyllactic acid, phytosphingosine, N-nonanoylglycine, sphinganine, S-carboxymethyl-L-cysteine] with p < 0.05 and AUC > 0.75, respectively. Evaluation of model performance for prediction of LAC resulted in a cross-validation classification accuracy of 87.9%. Metabolic pathway analysis showed that sphingolipid metabolism, fatty acid metabolism, carnitine synthesis and Warburg effect were most impacted in response to disease.Conclusion: This study indicates that the application of ND-EESI-MS to sputum analysis can be used as a non-invasive detection of peripheral lung nodules. The use of sputum metabolite biomarkers may aid in the development of a further evaluation program for lung adenocarcinoma.Keywords: lung cancer, metabolomics, ND-EESI-MS, diagnosis, non-invasive detection

Jiacheng Wu,1,2,* Haifei Xu,1,* Hao Ji,1 Baoqian Zhai,2 Jinfeng Zhu,1 Mingde Gao,3 Haixia Zhu,2 Xiaolin Wang1 1Department of Urology, Tumor Hospital Affiliated to Nantong University, Nantong University, Nantong 226361, People’s Republic of China; 2Cancer Research Center Nantong, Tumor Hospital Affiliated to Nantong University, Nantong University, Nantong 226361, People’s Republic of China; 3Department of Urology, Medical College of Nantong University, Nantong 226019, People’s Republic of China*These authors contributed equally to this workCorrespondence: Haixia ZhuCancer Research Center Nantong, Tumor Hospital Affiliated to Nantong University, Nantong University, No. 30 Tongyang Bei Road, Tongzhou District, Nantong 226361, People’s Republic of ChinaTel +86 138 6290 6771Fax +86 513 8671 2287Email zhx19891027@163.comXiaolin WangDepartment of Urology, Tumor Hospital Affiliated to Nantong University, Nantong University, No. 30 Tongyang Bei Road, Tongzhou District, Nantong 226361, People’s Republic of ChinaTel +86 159 5086 8500Fax +86 513 8672 9043Email cxhwyc2010@163.comObjective: To investigate the association between KRT17 and the prognosis in bladder cancer patients.Methods: The clinical data of 101 patients with bladder cancer from May 2013 to May 2015 were retrospectively analyzed. At the same time, the expression of KRT17 and its correlation with clinicopathological factors were examined by immunohistochemistry. We search the prognostic value of KRT17 in bladder cancer from the cancer genome map (TCGA) online database. To explore the possible cellular mechanism, gene set enrichment analysis (GSEA) was used. The patients were divided into two groups: high expression of KRT17 and low expression of KRT17. The patients were followed up for 5 years to observe the survival. Kaplan–Meier method and Log rank test were used for univariate survival analysis, and Cox regression analysis was used for multivariate analysis. Finally, a nomogram was constructed on this basis for internal verification.Results: Among the 101 patients, 46 (45.5%) were in the KRT17 low expression group and 55 (54.5%) in the high KRT17 expression group. After 5 years of follow-up, 79 patients survived with a survival rate of 78.2% and 22 patients died with a mortality rate of 21.8%. Kaplan–Meier survival analysis showed that OS and PFS of patients with high expression of KRT17 were significantly higher than those of patients with low expression of KRT17 (p< 0.001, p=0.005). Cox multivariate analysis showed that KRT17 expression was an independent risk factor for tumor progression (p=0.019). And tumor size, vascular tumor thrombus, and T stage also affected tumor progression (p< 0.05). In the internal validation, the c-index of nomogram was 0.898 (95% CI: 0.854– 0.941).Conclusion: The decreased expression of KRT17 is associated with poor prognosis in patients with bladder cancer. KRT17 can be used as a novel predictive biomarker to provide a new therapeutic target for bladder cancer patients.Keywords: keratin17, bladder cancer, overall survival, prognosis, progression-free survival, risk factors, nomograph

Haiming Ma,1 Tao Liu,2 Yanhua Xu,3 Xinying Wang,4 Jin Wang,1 Xiaokang Liu1 1Department of Oncology, Guangrao County People’s Hospital, Dongying City, Shandong Province 257300, People’s Republic of China; 2Department of General Surgery, Guangrao County People’s Hospital, Dongying City, Shandong Province 257300, People’s Republic of China; 3Department of Anesthesiology, Guangrao County People’s Hospital, Dongying City, Shandong Province 257300, People’s Republic of China; 4Department of Pathology, Guangrao County People’s Hospital, Dongying City, Shandong Province 257300, People’s Republic of ChinaCorrespondence: Xiaokang LiuDepartment of Oncology, Guangrao County People’s Hospital, No. 180 Huayuan Road, Guangrao County, Dongying City, Shandong Province 257300, People’s Republic of ChinaTel +86-18562040137Email jikang63797@163.comBackground: MiR-519d and miR-328-3p had tumor-regulatory properties in different cancers, but their combinatorial effects and potential common target in breast cancer had not been fully reported. This research targeted to study the underlying mechanism of how miR-519d and miR-328-3p cooperatively suppressed breast cancer.Methods: MiR-519d and miR-328-3p expressions in breast cancer tissues and cells were assessed and Ki-67 expression was also checked. DLR assay was executed to verify whether Ki-67 was a common target of miR-519d and miR-328-3p. Western blot, flow cytometry, colony formation, wound healing and transwell assays were applied to examine the inhibitory roles of these two miRNAs on the malignant behaviors of breast cancer cells and the potential molecular mechanism.Results: Impeded miR-519d and miR-328-3p expressions and enhanced Ki-67 expression were detected in breast cancer tissues and cells. Ki-67 was confirmed as a target of these two miRNAs. MiR-519d and miR-328-3p hampered cell proliferation and blocked cell cycle via binding to Ki-67 and they also suppressed migration and invasion. The combinatorial effects of two miRNAs were much stronger than a single miRNA.Conclusion: Our findings proved that miR-519d and miR-328-3p played combinatorial anti-cancer roles in breast cancer by directly targeting a common target Ki-67. Our study suggested that these two miRNAs might own the potential to become novel therapeutic biomarkers involved in the diagnosis and therapy of breast cancer.Keywords: breast cancer, miR-519d, miR-328-3p, Ki-67

Ming Zhao,1,* Mingxin Zhang,2,* Yonghua Wang,2 Xuecheng Yang,2 Xue Teng,2 Guangdi Chu,2,3 Xinsheng Wang,2 Haitao Niu2 1Department of Urology, Qingdao 8th People’s Hospital, Qingdao, People’s Republic of China; 2Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 3Department of Clinical Medicine, Qingdao University, Qingdao, People’s Republic of China*These authors contributed equally to this workCorrespondence: Haitao Niu; Xinsheng Wang Email niuht0532@126.com; Wangxs0532@163.comObjective: This study investigated the prognostic value of the preoperative albumin alkaline phosphatase ratio (AAPR) in patients with muscle-invasive bladder cancer after radical cystectomy.Materials and Methods: We performed a retrospective, single-center cohort study among patients with muscle-invasive bladder cancer who underwent radical cystectomy and urinary diversion at the Department of Urology Surgery of the Affiliated Hospital of Qingdao University from 2007 to 2015. Cox proportional hazards regression was used to evaluate the relationship between preoperative AAPR and outcomes which include OS and CSS and RFS. Survival analysis was conducted using the Kaplan–Meier method and the log rank test.Results: In total, 174 patients were followed up for 1– 125 months, with a median follow-up of 30 months, 93 survived and 81 patients died. The median serum AAPR level in all patients was 0.62 (range: 0.12– 1.67). In multivariate analysis, the preoperative AAPR showed to be associated with overall survival (OS: HR 0.22,95% CI 0.06 to 0.82, P=0.024), cancer-specific survival (CSS: HR 0.12,95% CI 0.02 to 0.63, P=0.013) and recurrence-free survival (RFS: HR 0.15,95% CI 0.03 to 0.82, P=0.029) after adjustment for potential confounders. Kaplan–Meier analysis showed that patients with low AAPR tertiles had shorter OS, CSS and RFS than patients with high AAPR tertiles (OS: P< 0.001, CSS: P< 0.001, RFS: P< 0.001). The relationship between AARP and OS, CSS and RFS was linear.Conclusion: Preoperative AAPR may be a potentially valuable prognostic marker in patients who underwent radical cystectomy for muscle-invasive bladder cancer.Keywords: albumin-to-alkaline phosphatase ratio, AAPR, muscle-invasive bladder cancer, radical cystectomy, prognosis

Xuejun Wang,1,* Hongmei Wang,1,* Baochang Jia,1 Fang He,2 Yawei Yuan,1 Weijun Zhang1 1Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, People’s Republic of China; 2Department of Radiation Oncology, Zhongshan City People’s Hospital, Zhongshan, Guangdong Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weijun Zhang; Hongmei WangDepartment of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong Province, People’s Republic of ChinaTel +86 136 8887 9087Email 591533086@qq.com; hongmeiW1988@163.comAbstract: Cutaneous metastasis from a primary visceral malignancy is a relatively uncommon clinical manifestation that occurs as an initial presentation in 1% to 12% of patients with internal malignancies. Additionally, cutaneous metastases are often late signs of an internal malignancy, and in very rare cases they may occur at the same time or before the primary cancer has been detected. Metastasis to the skin has a poor prognosis and is often a sign of widespread malignant tumors. In the present study, we report a 72-year-old male who presented with multiple rapidly growing subcutaneous nodules. Positron emission tomography-computed tomography (PET-CT) revealed a hypermetabolic concentration of radiotracer in the left lower lung and multiple organ metastases associated with multiple skin masses. Biopsy of one of the skin nodules and gene detection indicated metastatic adenocarcinoma consistent with a primary lung origin with a BRAF mutation. BRAF mutations are emerging therapeutic targets in non-small-cell lung cancer (NSCLC), as they are present in 2– 4% of NSCLC cases. To the best of our knowledge, this is the first case report to show that BRAF-mutant lung adenocarcinoma can be associated with cutaneous metastasis. Early diagnosis and individualized treatment strategies may prolong patient survival.Keywords: metastasis, skin lesion, lung adenocarcinoma, BRAF mutation

Guobin Zhong,1 Yuansheng Lin,2 Xu Wang,1 Keqiong Wang,1 Jianlun Liu,1,3 Wei Wei1 1Department of Breast Surgery, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China; 2Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China; 3Department of General Surgery, The Langdon Hospital of Guangxi Medical University, Nanning, People’s Republic of ChinaCorrespondence: Jianlun Liu; Wei Wei Email 2301881346@qq.com; 2871550164@qq.comPurpose: Breast cancer (BC) is the most common cancer in women. Emerging evidence has demonstrated that lncRNAs play an important role in BC. The objective of this study was to investigate the impact of the long non-coding RNA (lncRNA), H19/miRNA-130a-3P/special AT-rich sequence-binding protein-1 (SATB1) axis on BC progression.Materials and Methods: Expression of lncRNA and RNA was quantified via RT-qPCR. CCK-8, colony formation, wound healing, transwell, and flow cytometric analyses were used to analyze the proliferation, migration, invasion and apoptosis of cells. A dual-luciferase reporter assay and a RNA immunoprecipitation (RIP) assay were used to assess molecular binding. Protein levels were measured by Western blotting. The function of the lncRNA H19 (hereafter referred to as H19) was examined by xenotransplantation.Results: We demonstrated that H19 expression was higher in cancer tissues and cancer cell lines than in adjacent non-tumor tissues and normal cell lines, respectively. H19 silencing inhibited the proliferation, migration and invasion of BC cells, and induced apoptosis. In addition, H19 directly bound to miR-130a-3p and downregulated its expression. We further demonstrated that H19 sponged miRNA-130a-3p, which resulted in SATB1 upregulation, thus promoting BC progression. Silencing of H19 substantially suppressed BC tumorigenesis in vivo.Conclusion: Our data uncovered a novel mechanism of BC progression based on the H19-miR-130a-3p-SATB1 axis.Keywords: H19, breast cancer, long noncoding RNA, miR-130a-3p, SATB1

Huan Chen,1 Xi Wang,1 Huanhuan Jia,2 Yin Tao,3 Hong Zhou,3 Mingyuan Wang,4 Xin Wang,1 Xiaoling Fang1 1Department of Obstetrics and Gynecology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, People’s Republic of China; 2Guangdong Laboratory Animals Monitoring Institute, Guangdong Key Laboratory of Laboratory Animals, Guangzhou, Guangdong 510663, People’s Republic of China; 3Department of Obstetrics and Gynecology, Zhu Zhou Hospital Affiliated to Xiangya School of Medicine, CSU, Zhuzhou, Hunan 412007, People’s Republic of China; 4Department of Pathophysiology, School of Basic Medical Science, Central South University, Changsha, Hunan, 410013, People’s Republic of ChinaCorrespondence: Xiaoling Fang Tel +86 13973128345Email fxlfxl0510@csu.edu.cnBackground and Objective: Globally, cervical cancer (CC) is the fourth most common cancer affecting women. Although effective screening reduces its incidence, it remains one of the most serious cancers threatening the health of women. Therefore, the purpose of this study is to find new genes that can be used as potential biomarkers for the prognosis of CC.Methods and Results: After downloading three datasets such as GSE6791, GSE63678, and GSE63514 from the Gene Expression Omnibus (GEO), we combined the expression matrixes and analyzed them to obtain the differential expressed genes (DEGs). Next, using the STRING website, we performed the protein interaction network analysis. Subsequently, hub genes were screened using the R and Cytoscape software. Then, the expression difference and survival analyses of the hub genes were confirmed using GIPIA. Here, we established that the KNTC1 gene was correlated to the overall survival prognosis of CC. Besides, the expression of the KNTC1 gene in the GSE63514 dataset was significantly different from that of the normal cervix, cervical pre-cancerous lesions, and CC. Consequently, immunohistochemistry analysis showed that the results have a definite diagnostic value.Conclusion: The KNTC1 gene could be linked with the pathophysiology of CC and maybe one of the early diagnostic markers for the diagnosis of cervical pre-cancerous lesions.Keywords: cervical cancer, bioinformatics analysis, differentially expressed gene, pathways, KNTC1

Xin Wang, 1,* Song Yang, 1,* Xuechao Lv, 2 Lina Wang, 3 Chunmei Li 4 1Department of Plastic Maxillofacial Surgery, Heilongjiang Provincial Hospital, Harbin 150036, Heilongjiang, People’s Republic of China; 2Department of Pediatric Dentistry, School of Stomatology, Harbin Medical University, Harbin 150001, Heilongjiang, People’s Republic of China; 3Department of Oral and Maxillofacial Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang, People’s Republic of China; 4Department of Outpatient Stomatology, Heilongjiang Provincial Hospital, Harbin 150036, Heilongjiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chunmei LiDepartment of Outpatient Stomatology, Heilongjiang Provincial Hospital, Harbin 150036, Heilongjiang, People’s Republic of ChinaTel +86 451-8713-1023Email lichunmei2814@163.comBackground: As the most prevalent type of head and neck cancer, oral squamous-cell carcinoma (OSCC) accounts for nearly 90% of all oral cancer cases. Despite great progress having been made in the diagnosis and treatment of OSCC recently, the survival rate of OSCC patients has not risen remarkably. Chemotherapy is commonly used for OSCC treatment; however, the emergence of chemoresistance limits its long-term curative effect. Therefore, identifying effective biomarkers and molecular mechanisms is essential to the development of therapeutic strategies for OSCC.Methods: qRT-PCR assays were performed to detect SNHG1 expression in OSCC tissue and cells, and CCK8 assays and animal experiments used to examine cell proliferation. In addition, CCK8 assays were used to detect IC 50 values of cisplatin, 5Fu, Dox, and oncolytic adenovirus H101.Results: We found that SNHG1 was overexpressed in OSCC tissue and cells and was associated with OSCC progression. In addition, knockdown of SNHG1 suppressed cell proliferation in vitro and in vivo. Importantly, we found that oncolytic adenovirus H101 showed better antitumor effects in OSCC with high SNHG1 expression, and chemotherapy showed worse anti-tumor effects in OSCC with high SNHG1 expression.Conclusion: SNHG1 can act as a diagnostic biomarker for OSCC, and may be a biomarker for treatment options.Keywords: SNHG1, H101, OSCC

Tao Li,1 Qian Wu,2 Duanqin Liu,1 Xuxia Wang1 1Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, Shandong, People’s Republic of China; 2Department of Nursing, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of ChinaCorrespondence: Xuxia WangDepartment of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, No. 44-1 Wenhua Road West, Jinan, Shandong 250012, People’s Republic of ChinaFax +86 53188382923Email wxx@sdu.edu.cnBackground: MicroRNA27b-3p (miR-27b) has been reported to be dysregulated in multiple types of human cancer. However, the expression levels, biological roles, and underlying mechanism of miR-27b in tongue squamous cell carcinoma (TSCC) remain to be elucidated.Methods: Bioinformatics analyses and quantitative real-time PCR (qRT-PCR) were used to determine miR-27b expression in TSCC tissues and cell lines. The influence of miR-27b overexpression or inhibition on TSCC cell proliferation, migration, and invasion in vitro, and on tumor growth in vivo, was explored via CCK8, colony formation, wound healing, and transwell assays, and in xenograft tumors in nude mice, respectively. Luciferase reporter assays, qRT-PCR, and Western blotting were performed to clarify the potential mechanisms involving miR-27b in TSCC cells.Results: miR-27b was significantly downregulated in TSCC tissues and cell lines, and its expression was correlated with cancer status. Overexpression of miR-27b led to diminished proliferation, migration, and invasion, and notably reduced tumor growth in vivo. Bioinformatics analysis followed by luciferase reporter assays demonstrated that miR-27b expression was inversely correlated with that of integrin subunit α 5 (ITGA5)and that miR-27b directly bound to the 3ʹ-untranslated region of ITGA5 in TSCC cells. The bioinformatics analysis also indicated that ITGA5 was upregulated in TSCC and that its expression was correlated with epithelial–mesenchymal transition (EMT) and poor prognosis. Moreover, we found that miRNA-27b could reverse ITGA5-induced promotion of TSCC cell proliferation and migration. Finally, we demonstrated that regulation of miR-27b expression in TSCC may result in alterations in the expression of ITGA5 and EMT-related marker genes at the mRNA and protein levels.Conclusion: These results indicate that miR-27b hampers TSCC proliferation and migration via suppressing the EMT process by targeting ITGA5. These findings support consideration of miR-27b/ITGA5 as a valuable marker for the metastatic potential of TSCC, or as a therapeutic target for the treatment of TSCC.Keywords: miR-27b, epithelial–mesenchymal transition, integrin subunit alpha 5, bioinformatics analysis, tongue squamous cell carcinoma

Qijue Lu,* Xinyu Wang,* Ji Zhu,* Xiang Fei, Hezhong Chen, Chunguang Li Department of Thoracic Surgery, Changhai Hospital, The Second Military Medical University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chunguang LiDepartment of Thoracic Surgery, Changhai Hospital, The Second Military Medical University, No. 168 Changhai Road, Shanghai 200433, People’s Republic of ChinaTel +86 2131161764Email dr_lichunguang@sina.comIntroduction: Hypoxia and tumor-associated macrophage (TAM) are key regulators in remodeling the microenvironment of esophageal squamous cell carcinoma (ESCC). Hypoxia could stimulate tumor cells to secrete more exosomes and activate TAMs to M2 type. Here, we investigated the function and the underlying mechanism of tumor-derived exosomal hsa-circ-0048117 in TAM polarization in ESCC. Collectively, these data indicate that PC cells generate miR-301a-3p-rich exosomes in a hypoxic microenvironment, which then polarize macrophages to promote malignant behaviors of PC cells.Methods: Transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA) were used to analyze the physical characteristics of exosomes. High-throughput sequencing and bioinformatic analysis were performed to screen the potential exosomal circRNA. FISH, Ago2 RIP, pull-down and dual-luciferase reporter assay were conducted to figure out the correlation among hsa-circ-0048117, miR-140 and toll-like receptor 4 (TLR4). Flow cytometry and Western blot were used to evaluate their joint effect in macrophages polarization. Then, the invasion and migration ability were evaluated by transwell experiment. At last, serum exo-hsa-circ-0048117 in ESCC patients was compared and the correlation between its expression and T stage, N stage and TNM grades was analyzed.Results: Hsa-circ-0048117 was significantly upregulated and enriched in exosomes secreted by hypoxia pre-challenged tumor cells and contributed to M2 macrophage polarization. Hsa-circ-0048117 depletion in macrophage led to inhibition of M2 polarization while restoration of hsa-circ-0048117 could rescue the process. Moreover, hsa-circ-0048117 could act as sponge of miR-140 by competing with TLR4 to facilitate the M2 macrophage polarization. Exo-hsa-circ-0048117 could be transmitted to macrophages to promote M2 polarization and M2 macrophages could enhance the ability of invasion and migration of tumor cells by secreting Arg1, IL-10 and TGF-β. Higher serum exo-hsa-circ-0048117 predicted an advanced T and N stage and positively correlated with TNM grade.Conclusion: Our findings indicated that ESCC cells generate hsa-circ-0048117-rich exosomes in a hypoxic microenvironment; hsa-circ-0048117 was believed to promote M2 macrophage polarization which favors the malignant behaviors of ESCC cells. These results reminded us that exosomal hsa-circ-0048117 may play a key role in remodeling the microenvironment and modulating progression in ESCC.Keywords: esophageal squamous cell carcinoma, hypoxia, tumor-associated macrophage, exosomes, hsa-circ-0048117

Hao Su,1 Chen Chang,2 Jiajie Hao,2 Xin Xu,2 Mandula Bao,1 Shou Luo,1 Chuanduo Zhao,1 Qian Liu,1 Xishan Wang,1 Zhixiang Zhou,1 Haitao Zhou1 1Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China; 2State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Zhixiang Zhou; Haitao ZhouNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Panjiayuan Nanli, Chaoyang District, Beijing 100021, People’s Republic of ChinaTel/Fax +861087787110Email zhouzhixiangdoctor@126.com; zhouhaitao01745@163.comPurpose: The molecular mechanism of perineural invasion (PNI) in stage II colorectal cancer (CRC) remains not to be defined clearly. This study aims to identify the genomic aberrations related to PNI in stage II CRC.Patients and Methods: Using array-based comparative genomic hybridization (array-CGH), primary tumor tissues and paracancerous normal tissues of stage II CRC with PNI and without PNI were analyzed. We identified genomic aberrations by using Genomic Workbench and MD-SeeGH and validated the aberrations of selected genes by real-time polymerase chain reaction (PCR). Gene ontology (GO) and pathway analysis were performed to determine the most likely biological effects of these genes.Results: The most frequent gains in stage II CRC were at 7q11.21-q11.22, 8p11.21, 8p12-p11.23, 8q11.1-q11.22, 13q12.13-q12.2, and 20q11.21-q11.23 and the most frequent losses were at 17p13.1-p12, 8p23.2, and 118q11.2-q23. Four high-level amplifications at 8p11.23-p11.22, 18q21.1, 19q11-q12, and 20q11.21-q13.32 and homozygous deletions at 20p12.1 were discovered in Stage II CRC. Gains at 7q11.21-q22.1, 16p11.2, 17q23.3-q25.3, 19p13.3-p12, and 20p13-p11.1, and losses at 11q11-q12.1, 11p15.5-p15.1, 18p11.21, and 18q21.1-q23 were more commonly found in patients with PNI by frequency plot comparison together with detailed genomic analysis. It is also observed that gains at 8q11.1-q24.3, 9q13-q34.3, and 13q12.3-q13.1, and losses at 8p23.3-p12, 17p13.3-p11.2, and 21q22.12 occurred more frequently in patients without PNI. Further validation showed that the expression of FLT1, FBXW7, FGFR1, SLC20A2 and SERPINI1 was significantly up-regulated in the NPNI group compared to the PNI group. GO and pathway analysis revealed some genes enriched in specific pathways.Conclusion: These involved genomic changes in the PNI of stage II CRC may be useful to reveal the mechanisms underlying PNI and provide candidate biomarkers.Keywords: array CGH, colorectal cancer, perineural invasion, biomarker

Xiaofei Wang,1,* Xudong Song,1,* Guang Cheng,2,* Jingwen Zhang,3 Liru Dong,1 Jie Bai,1 Dan Luo,1 Yanjie Xiong,1 Shuang Li,1 Fang Liu,1 Yuanyuan Sun,1 Xin Wang,1 Yuyang Li,1 Yunning Huang4 1Department of Pathology, North China University of Science and Technology Affiliated Hospital, Tangshan 063000, Hebei, People’s Republic of China; 2Central Laboratory of Clinical Medical College, North China University of Science and Technology Affiliated Hospital, Tangshan 063000, Hebei, People’s Republic of China; 3School of Basic Medical Science, NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, NingXia Medical University, Yinchuan 750004, NingXia, People’s Republic of China; 4Department of Gastrointestinal Surgery, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan 750001, Ningxia, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yunning HuangDepartment of Gastrointestinal Surgery, People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan 750001, Ningxia, People’s Republic of ChinaEmail nxhyncc@126.comObjective: Increasing evidences suggest that mitochondrial calcium uniporter (MCU), a selective channel responsible for mitochondrial Ca2+ uptake, is involved in the progression of several cancers. In this study, we aimed to observe the clinical implications and biological functions of MCU in gastric cancer.Methods: The expression of MCU in 90 pairs of gastric cancer tissues and adjacent normal tissues was examined using immunohistochemistry and correlation between MCU expression and clinical features was analyzed. After construction of stable MCU knockdown or overexpression gastric cancer cells, mitochondrial membrane potential (MMP), wound healing and transwell assays were performed to examine MMP levels, migration and invasion. Subcutaneous xenograft tumors induced by gastric cancer cells transfected with MCU siRNAs or controls were constructed. Immunofluorescence was used to detect CD34 expression. Western blot was used to detect the expression of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), epithelial-mesenchymal transition (EMT)-related proteins.Results: MCU had a higher expression in gastric cancer tissues than normal tissues. Compared to gastric cancer tissues, its expression was significantly higher after omental metastasis. MCU expression was significantly correlated with depth of invasion (p=0.048), lymph metastasis (p=0.027), TNM stage (p=0.036) and distant metastasis (p=0.029). Patients with high MCU expression indicated a worse prognosis than those with its low expression (p=0.0098). MCU significantly increased the MMP levels of gastric cancer cells. Wound healing and transwell assay results showed that MCU promoted migration and invasion of gastric cancer cells. In vivo, MCU knockdown significantly inhibited tumor growth and angiogenesis. Both in vitro and in vivo, silencing MCU suppressed the expression of HIF-1α and VEGF as well as activity of EMT processes.Conclusion: Our findings suggested that highly expressed MCU could promote migration, invasion, angiogenesis and growth of gastric cancer, which could become a potential therapeutic marker for gastric cancer.Keywords: gastric cancer, mitochondrial calcium uniporter, invasion, angiogenesis, epithelial–mesenchymal transition

Lihua Yu,1,2,* Xiaoli Liu,1,* Yuyong Jiang,1,* Xinhui Wang,1 Xianbo Wang,1 Zhiyun Yang1 1Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, People’s Republic of China; 2First Clinical Medical College, Beijing University of Chinese Medicine, Beijing 100029, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhiyun YangCenter of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, People’s Republic of ChinaTel/Fax +86-10-84322148Email yangzhiyun2016@163.comBackground: Individuals with hepatocellular carcinoma (HCC) are at risk of tumor recurrence after surgical resection, which affects their survival. The aim of the present study was to establish a model for predicting tumor progression in patients with HCC.Methods: To develop and validate the efficacy of a novel prognostic model, a retrospective cohort with HCC (n = 1005) at Beijing Ditan Hospital was enrolled from January 2008 and June 2017. Furthermore, a prospective cohort (n = 77) was recruited to validate the association between thyroid-stimulating hormone (TSH) levels and tumor progression in patients with HCC.Results: The model used in predicting the progression of HCC included four variables (namely, Barcelona Clinic Liver Cancer [BCLC] stage, presence of portal vein tumor thrombus, alpha-fetoprotein level, and TSH level). The AUROC of the 1-year progression-free survival (PFS) model was 0.755 and 0.753 in the deriving cohort and validation cohort, respectively, and these values were significantly higher than those of the Child–Pugh score, Model for End-stage Liver Disease (MELD), tumor–lymph node–metastasis (TNM) staging system, Okuda classification, and CLIP score. A simple assessment using a nomogram showed the 1-year PFS rate of patients with HCC. In the prospective cohort, the KM curve showed that the high TSH level group had a shorter PFS than the low TSH level (p = 0.001).Conclusion: The prognostic model of HCC progression was superior to other well-known classical tumor scoring systems. A high TSH level was correlated to poor outcome, particularly those with advanced HCC.Keywords: hepatocellular carcinoma, thyroid hormone, tumor progression model

Yang Zhang, Zhenguo Shi, Zhijun Li, Xiaohui Wang, Pengyi Zheng, Huibing Li Department of Urology Surgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, People’s Republic of ChinaCorrespondence: Zhijun Li Tel +86 379-64830626Email pmuzhsa@163.comBackground: Prostate cancer (PCa) is one of the most common malignant cancer in males worldwide. Circular RNAs (CircRNAs) are novel type of non-coding RNAs. Recently, circRNAs have been reported participating in various cancers, including prostate cancer. However, the function and mechanism of circ_0057553 remain to be elucidated.Methods and Materials: The RNA expression levels of circ_0057553, miR-515-5p, YES proto-oncogene 1 (YES1) and glycolytic genes mRNA were detected by qRT-PCR in PCa tissues or cells. Western blotting was performed to analyze YES1 protein level. Cell viability, migration and invasion and cell apoptosis were assessed by cell counting kit-8 (CCK-8) assay, transwell assay and flow cytometry. In addition, the effects of cell glycolysis were evaluated by measuring lactate production, glucose consumption and adenosine triphosphate (ATP) level. Moreover, dual-luciferase reporter assay was used to detect the target sites of circ_0057553 and miR-515-5p, miR-515-5p and YES1. RNA immunoprecipitation (RIP) was conducted to evaluate the target relationship between circ_0057553 and miR-515-5p. Xenograft mouse model was conducted to measure tumor formation in vivo.Results: Circ_0057553 was significantly up-regulated in PCa tissues and cells. Knockdown of circ_0057553 inhibited cell viability, migration, invasion and glycolysis and facilitated apoptosis in PCa cells. Furthermore, circ_0057553 bound to miR-515-5p and miR-515-5p directly targeted YES1. Interestingly, miR-515-5p inhibitor partially rescued the function of circ_0057553 knockdown, while YES1 restored the effects of miR-515-5p overexpression. Circ_0057553 down-regulation remarkably decreased tumor volume and weight in vivo.Conclusion: Circ_0057553 affected PCa cell viability, migration, invasion, apoptosis and glycolysis through miR-515-5p/YES1 axis.Keywords: circ_0057553, miR-515-5p, YES1, prostate cancer

Ting Han,1 Zhengwu Cheng,1 Menglin Xu,2 Xiaoming Wang,3 Jian Wu,1 Xiaosan Fang3 1Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu 241000, People’s Republic of China; 2Department of Oncology, The First Affiliated Hospital of Wannan Medical College, Wuhu 241000, People’s Republic of China; 3Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College, Wuhu 241000, People’s Republic of ChinaCorrespondence: Xiaosan FangDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College, No. 2 Zheshan West Road, Jinghu District, Wuhu 241000, Anhui Province, People’s Republic of ChinaEmail xiaosanfang2020@163.comObjective: In the present study, we aimed to explore the potential oncogenic property and the internal mechanism of yes-associated protein (YAP) in gastric cancer (GC).Materials and Methods: YAP protein levels were evaluated in human GC tissues and paired normal tissues using immunohistochemistry (IHC). The role of YAP in regulating GC cell proliferation and migration was verified by genetic manipulation in vitro. Western blot analysis was used to determine the molecular signaling to explain the mechanism of the observed YAP effects in GC.Results: Nuclear YAP protein expression was upregulated in GC tissues, and high nuclear YAP level was significantly correlated with lymph node metastasis (LNM) and tumor node metastasis (TNM) stage in patients suffered from GC. YAP knockdown inhibited GC cell proliferation, migration and epithelial–mesenchymal transition (EMT) progress in vitro, whereas YAP elevation did the opposite. YAP regulated glioma-associated oncogene-1 (Gli1) expression independent of smoothened homolog (SMO). YAP modulated protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling pathway in GC cells.Conclusion: YAP enhanced GC cell proliferation and migration potentially via its regulation of Gli1 expression through the non-classical Hedgehog pathway, indicating suppression of YAP/Gli1 signaling axis may highlight a new entry point for combination therapy of GC.Keywords: YAP, proliferation, migration, Hedgehog pathway, gastric cancer

Jianwen Wang, Xuehai Wang, Kai Liu, Li Gu, Lei Yu, Li Han, Zhaojin Meng Department of Otolaryngology, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai 264200, Shandong, People’s Republic of ChinaCorrespondence: Xuehai WangDepartment of Otolaryngology, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai 264200, Shandong, People’s Republic of ChinaEmail xuehai581@163.comIntroduction: Radiotherapy is one of the most important methods in the treatment of patients with hypopharyngeal squamous cell carcinoma (HSCC). However, radioresistance will be developed after repeated irradiation. Among many key factors contributing to radioresistance, enhanced autophagy is recognized as one of the most important. The ultraviolent irradiation resistance-associated gene (UVRAG) is reported to be a crucial gene involved in the process of autophagy. Here, we test whether UVRAG has effect on the radioresistance of HSCC.Methods: HSCC cell line Fadu cells were treated with irradiation to test levels of autophagy. Tumor tissues from primary and recurrent HSCC patients were tested by immunohistochemistry. Then, we knocked down UVRAG to test its role in cell growth and the malignant behaviors. Response of cells to treatment was examined using LDH release assay, immunofluorescence, Western blot analysis and colony formation.Results: We found that irradiation induced autophagy in Fadu cells. Immunohistochemistry of primary and irradiated HSCC tumor tissues showed that UVRAG was upregulated after irradiation treatment. Inhibiting UVRAG with siRNA interfered cell growth, cell cycle, malignant behaviors and autophagic flux in Fadu cells. Knocking down UVRAG increased DNA damage and cell death induced by irradiation. Finally, we found that inhibiting UVRAG induced lysosomal membrane permeabilization, which contributed to radiosensitization of Fadu cells.Conclusion: Our findings supported the oncogenic properties of UVRAG in HSCC and inhibiting UVRAG increased radiosensitivity in HSCC by triggering lysosomal membrane permeabilization. Therefore, UVRAG might be a promising target in the treatment of HSCC.Keywords: UVRAG, autophagy, radiosensitivity, hypopharyngeal squamous cell carcinoma, lysosomal membrane permeabilization

Xun Wang,1,* Xiao Li,1,* Haifa Guo,1,* Lingxiang Zhu,2 Zhiyong Peng,3 Jun Wang,1 Fan Yang,1 Yong Guo4 1Department of Thoracic Surgery, Peking University People’s Hospital, Peking University, Beijing 100044, People’s Republic of China; 2National Research Institute for Health and Family Planning, Beijing 100081, People’s Republic of China; 3TargetingOne Corporation, Beijing 100190, People’s Republic of China; 4Department of Biomedical Engineering, School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University, Beijing 100084, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fan YangDepartment of Thoracic Surgery, Peking University People’s Hospital, Peking University, Beijing 100044, People’s Republic of ChinaEmail yangfanpkuph@sina.comYong GuoDepartment of Biomedical Engineering, School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University, Beijing 100084, People’s Republic of ChinaEmail yongguo@tsinghua.edu.cnObjective: The aim of this study was to investigate the allelic relation between de novo T790M and concomitant sensitizing EGFR mutations in EGFR-TKIs naïve NSCLCs and to explore whether the formalin-fixed and paraffin-embedded (FFPE) materials affect the detection of de novo T790M mutation.Methods: Specimens of 300 consecutive EGFR-TKI naïve NSCLCs who received surgical resection between January 2016 and June 2018 were retrospectively investigated. All the snap-frozen tumor tissues from 300 NSCLCs were screened by droplet digital PCR (ddPCR) for the detection of de novo T790M mutation. The allelic relation between de novo T790M mutation and concomitant sensitizing EGFR mutations was also investigated. Furthermore, we assessed de novo T790M mutation in paired FFPE specimens of 50 patients which included tumor tissues and paired normal lung tissues of the pretreatment NSCLCs to investigate whether FFPE materials affect the detection of de novo T790M mutation.Results: The de novo T790M mutation was observed in four patients which included one patient of single de novo T790M mutation and three patients of de novo T790M mutation coexisting with L858R mutation. The incidence of de novo T790M in pretreatment NSCLCs who harboring EGFR mutations was 2.9% (4/139). All the de novo T790M mutations were detected in cis with the concomitant L858R mutations for the three NSCLCs. Our ddPCR method demonstrated that the frequency of de novo T790M mutation was ranging from 0.1% to 0.5% among 90% (45/50) of the FFPE tumor samples and 92% (46/50) of the paired FFPE adjacent normal lung samples. The frequency of de novo T790M mutation in the paired snap-frozen samples was all below 0.1%.Conclusion: Our study demonstrated that most de novo T790M mutations were detected in cis with concomitant sensitizing mutations for pretreatment NSCLCs. Analytical cut-off of ddPCR assay for FFPE specimens should be validated carefully considering the possibility of FFPE-derived artificial gene mutations.Keywords: non-small cell lung cancer, NSCLC, droplet digital PCR, de novo T790M, acquired T790M, EGFR mutation

Xiuyong Wang, Yuan Chang, Ming Gao, Fan Zhang Department of Dermatology, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, Henan 471000, People’s Republic of ChinaCorrespondence: Xiuyong Wang Department of DermatologyLuoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, Henan 471000, People’s Republic of ChinaEmail wangxiuyo@sina.comPurpose: Cutaneous squamous cell carcinoma (cSCC) is the most common second basal cell carcinoma in our population. Wogonoside, the main in vivo metabolite of wogonin, possesses anti-inflammatory, anti-angiogenesis and anti-cancer activities. Nevertheless, the effectiveness of wogonoside therapy on cSCC has not been clarified.Methods: In this study, we investigated the effects of wogonoside on cell proliferation, invasion, epithelial–mesenchymal transition (EMT) and cancer stem-like cell (CSC) properties of SCL-1 and SCC12 cell lines, and the effects on tumor formation in vivo. In vitro, cells were treated with 0, 25, 50 and 100 μM wogonoside for 48 h. In vivo, SCL-1 cells were subcutaneously injected into the right thigh of mice to form xenograft tumors. Animals were randomly divided into two groups (n=10): the control group and the 80 mg/kg wogonoside group.Results: The results showed that wogonoside attenuated proliferation, invasion and EMT of SCL-1 and SCC12 cell lines, and enhanced the rate of apoptosis. Meanwhile, wogonoside efficiently abolished the CSC traits of cSCC; the expression of CSC markers (ALDH1, SOX-2, Oct4 and CD44) and the percentage of CD133+ cells were remarkably downregulated. In addition, we found that wogonoside repressed the activation of both PI3K/AKT and Wnt/β-catenin pathways. In vivo, wogonoside significantly inhibited tumor formation.Conclusion: The results indicated that wogonoside could attenuate cSCC by reducing EMT, invasion and CSC properties. The efficacy of intervention may be related to inhibition of the PI3K/Akt and Wnt/β-catenin pathways. These novel findings could furnish new ideas on the potential therapeutic application of wogonoside in cSCC cancellation and cancer intervention.Keywords: cSCC, ALDH1, Wnt/β-catenin pathway, PI3K/AKT pathway, EMT

Xin Wang,1,* Ya Cheng,1,* Liang-liang Yan,2 Ran An,1 Xing-yu Wang,1 Heng-yi Wang1 1Department of Emergency Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, People’s Republic of China; 2Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Heng-yi Wang Tel +86-156-0551-1180Email why00606@sina.comBackground: Hepatocellular carcinoma (HCC) includes cryptogenic hepatocellular carcinomas (CR-HCC) that lack a defined cause. Specific DNA methylation patterns and comparisons of the aberrant alterations in DNA methylation between CR-HCC and adjacent peritumor tissues (APTs) have not yet been reported.Methods: The SureSelectXT Methyl-Seq Target Enrichment System was used to sequence targeted DNA methylation in three paired CR-HCC tissues and APTs. Gene Ontology (GO) enrichment and KEGG pathway analysis were performed to investigate the DNA methylation mechanism of CR-HCC. The mRNA expression levels of HOXB-AS3, HOXB6, HOXB3, USP18, MAP3K6, TIRAP, TNNI2, SHC3, CTTN, and TFAP2A, selected from the identified signaling pathways, were evaluated by quantitative real-time PCR (qPCR).Results: A total of 1728 differentially methylated regions (DMRs) were identified in tumor tissues compared with non-tumor tissues, of which 868 DMRs were hypermethylated and 860 were hypomethylated. The DMRs were mapped within 2091 DMR-associated genes (DMGs). The mRNA expression of HOXB-AS3, HOXB3, and MAP3K6 was downregulated in CR-HCC tissues compared to the APTs. However, the mRNA expression of TIRAP, SHC3, and CTTN was upregulated in the CR-HCC tissues. Differences between the mRNA expression of HOXB6, USP18, TNNI2, and TFAP2A in the CR-HCC and APTS tissues were not statistically significant. GO analysis showed that the molecular functions of “binding”, “protein binding”, and “cytoskeletal protein binding” were the main categories for the hypermethylated DMGs. The hypomethylated DMGs were mostly enriched in the molecular functions “binding”, “protein binding”, “calcium ion binding”, among others. KEGG pathway analysis showed that the hypermethylated DMGs were enriched in several pathways such as “estrogen signaling pathway”, while hypomethylated DMGs were enriched in several pathways such as “proteoglycans in cancer”, suggesting that epigenetic modifications play important roles in the cryptogenic hepatocarcinogenesis.Conclusion: These results provide useful information for future work to characterize the functions of epigenetic mechanisms on CR-HCC.Keywords: cryptogenic hepatocellular carcinomas, DNA methylation, DMR

Xuewen Wang,1,* Bing Chen,1– 3,* Danfen Xu,1 Zhijun Li,4 Yuxia Sui,5,6 Xinhua Lin1– 3 1Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 2Nano Medical Technology Research Institute, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 3Higher Educational Key Laboratory for Nano Biomedical Technology of Fujian Province, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 4School of Pharmacy, Fujian Medical University, Fuzhou 350180, Fujian, People’s Republic of China; 5Department of Pharmacy, Shengli Clinical Medical College of Fujian Medical University, Fuzhou 350001, People’s Republic of China; 6Department of Pharmacy, Fujian Provincial Hospital, Fuzhou 350001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xinhua LinDepartment of Pharmaceutical Analysis, Fujian Medical University, No. 1 Xueyuan Road, University Town, Fuzhou 350122, People’s Republic of ChinaTel/Fax +86 13906909638Email xhlfz123454321@sina.comYuxia SuiDepartment of Pharmacy, Fujian Provincial Hospital, No. 134 Dong Street, Fuzhou 350001, People’s Republic of ChinaTel/Fax +86 15959090652Email suiyuxia123@163.comBackground: The incidence and mortality of lung cancer continue to increase around the world; in 2018, new lung cancer cases accounted for 11.6% of all cancer cases, and lung cancer deaths accounted for 18.4% of cancer deaths. Cisplatin (DDP) is a first-line chemotherapy drug for lung cancer; however, DDP resistance can lead to a poor prognosis in patients with lung cancer. Therefore, reversing DDP resistance is a treatment goal.Materials and Methods: Cell counting kit-8 (CCK8) assays, wound healing analyses, Transwell assays, in vitro tumor xenografts, and flow cytometry were used to detect the proliferation, migration, invasion, and apoptosis of multidrug resistant A549/DDP and PC9/DDP cells, respectively. Western blot was performed to detect protein levels of cleaved caspase-3, CHOP, and GRP78.Results: Delicaflavone inhibited DDP resistance of lung cancer cells and decreased proliferation in a dose- and time-dependent manner. It also decreased migration and invasion and enhanced apoptosis. Western blots showed that delicaflavone overcame DDP resistance by increasing the expression of GRP78 and CHOP and the apoptosis-related protein cleaved caspase-3.Conclusion: Delicaflavone can reverse DDP resistance in A549/DDP and PC9/DDP cells by inhibiting cell proliferation and migration and enhancing apoptosis and cleaved caspase-3 levels by increasing the expression of CHOP and GRP78 protein via the endoplasmic reticular stress pathway. It could be a useful therapeutic adjunct to treat DDP-resistant lung cancer.Keywords: delicaflavone, Cisplatin; DDP, lung cancer, endoplasmic reticulum stress

Qinchen Lu,1– 3,* Jiamin Gao,1– 3,* Shaomei Tang,4,* Zhijian Li,2,3 Xi Wang,2,3 Caiwang Deng,2,3 Jiaxin Hu,1– 3 Yuting Tao,2,3 Qiuyan Wang1– 3 1Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Guangxi Medical University, Nanning 530021, People’s Republic of China; 2Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning 530021, People’s Republic of China; 3Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Nanning 530021, People’s Republic of China; 4Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qiuyan Wang; Yuting TaoCenter for Genomic and Personalized Medicine, Guangxi Medical University, 22 Shuangyong Road, Nanning 530021, People’s Republic of ChinaTel/Fax +86 7715353342Email qiuyanwang510@yahoo.com; tytxzxh@126.comPurpose: Accumulating evidence indicates that long non-coding RNAs (lncRNAs) play critical roles in the development of many cancer types. However, the changes of lncRNAs expression profiles in hepatocarcinogenesis remain largely unknown. Therefore, the purpose of this study was to identify the clinical significance, oncogenic functions, and potential mechanism of cancer-related lncRNAs in hepatocellular carcinoma (HCC).Materials and Methods: An in vitro hepatocellular carcinoma model was established via oncogene-mediated transformation with a combination of three genetic alterations, including hTERT overexpression, inactivation of P53, and KRAS activation. Changes of biological function and transcriptome profile in these cell lines were determined by colony formation assay, MTT assay, wound-healing scratch assay, xenograft nude mice model, mass cytometry and RNA sequencing (RNA-Seq). Furthermore, 116 HCC tissues and its corresponding normal tumor-adjacent tissues were explored to validate the results of cell lines. Finally, RNA sequencing, single-cell mass cytometry and fluorescence-activated cell sorter were applied to evaluate the potential association between the expression of lncRNA and the stemness of HCC.Results: LncRNA HOXA-AS2 was aberrantly upregulated and it may be involved in the regulation of cancer stem cells during oncogenic transformation. Consistently, lncRNA HOXA-AS2 expression was significantly upregulated in HCC and its higher expression positively correlated with poor prognosis and stem cell-related functions. Moreover, a specific cancer stem cell subpopulation with EPCAM+, C-MYC+ and CK19+ may exist in higher HOXA-AS2 expression HCC patients.Conclusion: LncRNA HOXA-AS2 plays pivotal roles in the occurrence and progression of HCC, which may act as a therapeutic target for prognostic biomarker in hepatocellular carcinoma.Keywords: diagnostic markers, hepatocellular carcinoma, lncRNA HOXA-AS2, multi-omics analysis, oncogenic transformation, stemness

Jun Yang,1 Junwen Chen,2 Si Wu,3 Xiang Fei,2 Xia Wang,2 Kefeng Wang2 1Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, People’s Republic of China; 2Department of Urology, Shengjing Hospital of China Medical University, Shenyang 110004, People’s Republic of China; 3Department of Biobank, Shengjing Hospital of China Medical University, Shenyang 110004, People’s Republic of ChinaCorrespondence: Kefeng WangDepartment of Urology, Shengjing Hospital of China Medical University, 36# Sanhao Street, Heping District, Shenyang, Liaoning, People’s Republic of ChinaTel +86 18940254849Fax +86 24 31939077Email wang.kefeng@hotmail.comBackground: Increasing evidence shows that circular RNAs (circRNAs) are involved in many biological processes, functioning as microRNA (miRNA) sponges. The aim of this study is to identify differentially expressed circRNAs in bladder cancer (BCa).Methods: The transcriptome of circRNAs in BCa was assayed by microarray. Quantitative real-time PCR was performed to verify the results. Then, potential miRNA response elements (MREs) between circRNAs and miRNAs were predicted. Pathway and ontology enrichment analyses were performed to identify mechanisms related to the gene regulation of differentially expressed circRNAs.Results: Three hundred and eighty-six up-regulated and 394 down-regulated circRNAs were identified, and their potential MREs were predicted in BCa.Conclusion: The differentially expressed circRNAs indicate that circRNAs could play important roles in the molecular pathogenesis of BCa.Keywords: bladder cancer, microarray, noncoding RNAs, circular RNAs, bioinformatics analysis

Xiaoming Wang,* Yunjin Bai,* Facai Zhang, Yubo Yang, Dechao Feng, Ao Li, Zhiqiang Yang, Dengxiong Li, Yin Tang, Xin Wei, Wuran Wei, Ping Han Department of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ping HanDepartment of Urology/Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, People’s Republic of ChinaTel +86 18980601955Fax +86 28 85582944Email hanpingwch@163.comBackground: Bladder cancer (BC) is a common malignancy worldwide that accounts for 3% of global cancer diagnoses. Chemotherapy resistance limits the therapeutic effect of chemotherapeutic agents in patients with BC. Prolyl 4-hydroxylase, beta polypeptide (P4HB) is an endoplasmic reticulum (ER) chaperone that is upregulated in bladder cancer tissues (The Cancer Genome Atlas, TCGA datasets). Knockdown or suppression of P4HB exerts anticancer activity and sensitizes cells to chemotherapy in various types of cancer.Purpose: We aimed to investigate whether the inhibition of P4HB enhances the anticancer efficacy of gemcitabine (GEM) in BC cells and to study the underlying molecular mechanisms.Patients and Methods: The P4HB mRNA expression levels of 411 BC patients from the TCGA database and P4HB expression level of eighty BC paraffin-embedded samples detected by immunohistochemistry (IHC) staining were used for clinical feature and prognostic analyses. Bioinformatics analysis was utilized for the mechanistic investigation. Highly P4HB-expressed BC cell lines (T24 and 5637) treated with P4HB inhibitor (Bacitracin, BAC) were used to study the effects of BAC on the sensitivity of BC cells to GEM and the potential mechanism. P4HB inhibition experiments were performed in highly P4HB-expressed BC cells, and cell viability, colony formation, cell cycle, reactive oxygen species (ROS), apoptosis and pathway proteins were assessed in T24 and 5637 cells.Results: Western blot analysis showed that P4HB expression was significantly higher in BC tissues than in paired normal tissues. IHC showed that patients with high P4HB expression had a poorer overall survival (OS) rate than those with low P4HB expression. Furthermore, increased P4HB expression was demonstrated to be an independent prognostic marker for BC. Functionally, P4HB inhibition by BAC decreased the cell proliferation ability in vitro. Moreover, BAC treatment sensitized BC cells to GEM. Molecular mechanism analysis indicated that inhibition of P4HB by BAC treatment enhanced the anticancer effects of GEM through increasing cellular ROS content and promoting cell apoptosis and PERK/eIF2α/ATF4/CHOP signaling.Conclusion: High P4HB expression was significantly correlated with poor prognosis in BC patients. Inhibition of P4HB by BAC decreased the cell proliferation ability and sensitized BC cells to GEM by activating apoptosis and the PERK/eIF2α/ATF4/CHOP pathways.Keywords: P4HB, ER stress, bladder cancer, gemcitabine, bacitracin

Gang Wang,1– 4,* Rui Cao,5,* Kaiyu Qian,1– 4,* Tianchen Peng,6 Lushun Yuan,6 Liang Chen,6 Songtao Cheng,6 Yaoyi Xiong,6 Lingao Ju,1– 4 Xinghuan Wang,6 Yu Xiao1– 4,6 1Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China; 2Human Genetics Resource Preservation Center of Wuhan University, Wuhan, People’s Republic of China; 3Human Genetics Resource Preservation Center of Hubei Province, Wuhan, People’s Republic of China; 4Cancer Precision Diagnosis and Treatment and Translational Medicine Hubei Engineering Research Center, Wuhan, People’s Republic of China; 5Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China; 6Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yu Xiao; Xinghuan Wang Tel +86-27-6781-2689; +86-27-6781-3104Fax +86-27-6781-2892Email yu.xiao@whu.edu.cn; wangxinghuan@whu.edu.cnIntroduction: Based on accumulating evidence, transient receptor potential (TRP) ion channels may play important roles in the occurrence and the progression of cancer. TRP melastatin 8 (TRPM8), a member of the TRP family, functions as a Ca2+-permeable channel and regulates various physiological and pathological processes. However, the effects of TRPM8 on bladder cancer (BCa) and its underlying mechanisms have not been elucidated.Methods: BCa tissues and matched noncancerous tissues were collected to examine the expression of the TRPM8 mRNA and protein using qRT-PCR, Western blotting and immunofluorescence staining. Meanwhile, the effect of knockdown or inhibition of the activity of the TRPM8 protein on the proliferation, migration and ROS metabolism of bladder cancer cells was detected using the MTT assay, clonogenic survival assay, Transwell chamber migration assay, and reactive oxygen species (ROS) detection, respectively. Furthermore, a mouse model transplanted with BCa cells was established to assess tumor growth after TRPM8 expression was inhibited in vivo.Results: Compared with the noncancerous tissues, the levels of TRPM8 in BCa tissues were significantly increased. Knockdown or inhibition of the activity of the TRPM8 protein in BCa cells reduced cell proliferation and migration. Moreover, the production of ROS was increased in cells treated with siTRPM8, which was accompanied by increased levels of Catalase, HO-1 and SOD2. Furthermore, a mouse model transplanted with the stable TRPM8-deficient T24 cell line was established, demonstrating that knockdown of TRPM8 delayed tumor growth in vivo.Discussion: TRPM8 might play an essential for BCa tumor progression and metastasis by interfering with BCa cell proliferation, motility, ROS metabolism and migration.Keywords: bladder cancer, TRPM8, proliferation, migration, reactive oxygen species

Tao Zhang,1,* Li Zhao,2,* Taotao Zhang,1,* Wangyu Wu,1 Jie Liu,3 Xian Wang,1 Yang Wan,4 Hao Geng,1 Xin Sun,1 Weiwei Qian,1 Dexin Yu1 1Department of Urologic Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei 230032, People’s Republic of China; 2Department of Urologic Surgery, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, 210048, People’s Republic of China; 3Department of Urologic Surgery, The First People’s Hospital of Wuhu, Wuhu 241000, People’s Republic of China; 4Department of Hematology/Hematological Lab, The Second Affiliated Hospital of Anhui Medical University, Hefei 230032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dexin YuDepartment of Urologic Surgery, The Second Affiliated Hospital of Anhui Medical University, 80 Feicui Road, Hefei 230032, People’s Republic of ChinaEmail uroman_urology@163.comBackground: So far, little research has been conducted regarding the underlying mechanism of renal carcinogenesis at molecular level. Epithelial–mesenchymal transition (EMT) exerts an important part during tumor genesis as well as the development through mitogen-activated protein kinase (MAPK) pathways. Therefore, we hypothesized that EMT could promote renal cell carcinoma (RCC) progression via the ERK5/AP-1pathway.Materials and Methods: The RCC cell lines were utilized to be the models with in vitro exposure to cigarette smoke extract (CSE). We used the curcumin for the EMT intervention study. In the present study, immunohistochemistry (IHC), Western blotting, and real-time quantitative reverse transcription PCR had been used to determine the experimental results. EMT phenotypic alterations were assessed by changes in cell morphology, invasion and transfer ability, as well as expression of epithelial and mesenchymal markers.Results: In human renal cell carcinoma tissue, E-cadherin expression within the smoking renal cancer patients was down-regulated compared with that among the non-smokers. However, Vimentin, N-cadherin, and TWIST levels increased (P< 0.05). Significantly, we clarified that ERK5/AP-1 exerted positive regulation on the renal cell carcinoma EMT mediated by CS, which was suggested based on the results of CS activating the ERK5/AP-1 pathway, as well as ERK5 inhibition via XMD8-92 reversed AP-1 protein levels and the EMT process. Furthermore, curcumin showed the same inhibitory effect as XMD8-92 and significantly reversed CS-induced EMT through inhibiting the ERK5/AP-1 signaling pathway.Conclusion: The above results indicated that ERK5/AP-1 signaling pathway exerts a vital part for CS-associated RCC development and cancer intervention.Keywords: renal cell carcinoma, epithelial–mesenchymal transition, cigarette smoke, ERK5/AP-1 pathway, curcumin

Shulin Li,1 Yuqi Wu,1 Jiawei Zhang,1 Hao Sun,2 Xiangwei Wang1 1Department of Urology & Carson International Cancer Center, Shenzhen University General Hospital & Shenzhen University Clinical Medical Academy Center, Shenzhen University, Shenzhen 518000, People’s Republic of China; 2Department of Urology, Shenzhen Second People’s Hospital & the First Affiliated Hospital of Shenzhen University, Shenzhen 518000, People’s Republic of ChinaCorrespondence: Xiangwei WangDepartment of Urology & Carson International Cancer Center, Shenzhen University General Hospital & Shenzhen University Clinical Medical Academy Center, Shenzhen University, No. 1098, Xueyuan Road, Shenzhen University City, Nanshan District, Shenzhen 518000, People’s Republic of ChinaTel +86 17796349157Fax +86 075521839000Email winn0324@szu.edu.cnAbstract: microRNA (miRNA) is an important part of non-coding RNA that regulates gene expression at a posttranscriptional level. miRNA has gained increasing interest in recent years, both in research and clinical fields. miRNAs have been found to play an important role in various diseases, particularly cancer. Aberrant miR-424 expression is found in several tumors where they can function as either oncogenes or tumor-suppressor genes. Meanwhile, miR-424 is also affected by the reorganization of many other non-coding RNAs such as lncRNA and cirRNA. Several studies have found that miR-424 participates in proliferation, differentiation, apoptosis, invasion, angiogenesis, and drug resistance, and plays an important role in the tumorigenesis and progression of tumors. This review will focus on the recent progress of research on miR-424 in tumors.Keywords: miRNAs, miR-424, tumor, regulation, carcinogenesis, cancer progression

Junwei Hu,1,2,* Zeyu Wang,1,* Jinjun Wang,3 Yicheng Jian,1,2 Jiarun Dai,1,2 Xiaoping Wang,1,2 Wujun Xiong4 1Department of Gastroenterology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, People’s Republic of China; 2Department of Digestive Endoscopy, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, People’s Republic of China; 3Department of Gerontology, Shanghai Putuo Central Hospital Affiliated to Shanghai Traditional Chinese Medicine University, Shanghai 200062, People’s Republic of China; 4Department of Hepatology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoping WangDepartment of Gastroenterology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, People’s Republic of ChinaTel +86 2168135590Email xhnk001@163.comWujun XiongDepartment of Hepatology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, People’s Republic of ChinaEmail xiongwujun@126.comPurpose: Hepatocellular carcinoma (HCC) is the most common primary liver tumor and the third greatest cause of cancer-related death worldwide. Programmed cell death 4 (PDCD4) was reported as a potential tumor-suppressor in hepatocarcinogenesis. However, relatively little is known about mechanisms that regulate PDCD4 expression in HCC. The aim of the present study is to investigate the expression of PDCD4 and miR-182 in human HCC cell lines and clinical HCC specimens and determine whether PDCD4 is a direct target of miR-182 in HCC cell lines.Materials: The expression of miR-182 and PDCD4 in human HCC cell lines and HCC tissues were examined using qRT-PCR and Western blot method. Transwell and wound healing assays were carried out to explore the influence of miR-182 on hepatoma cells migration. A luciferase reporter assay was conducted to confirm target association.Results: In our research, we found that PDCD4 was downregulated, whereas miR-182 was upregulated in liver cancer cell lines and HCC tissues. Transwell and wound healing assays illustrated that miR-182 contributed to migration activities of liver cancer cell lines. Loss or increase of miR-182 can lead to a negative expression of PDCD4 protein level. The luciferase reporter assay showed that PDCD4 is a direct target of miR-182.Conclusion: All these findings suggest that miR-182 may act as an oncogenic role in liver cancer cells by directly and negatively regulating expression of PDCD4.Keywords: miR-182, migration, PDCD4, hepatocellular carcinoma

Jianjian Yang, Xue Wang, Yi Gao, Can Fang, Fan Ye, Bing Huang, Lequn Li Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of ChinaCorrespondence: Lequn LiDepartment of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jie Fang Avenue, Wuhan, Hubei 430030, People’s Republic of ChinaTel + 86-15172330682Email lqli@tjh.tjmu.edu.cnPurpose: Cyclooxygenase-2 (COX-2) and its enzymatic product prostaglandin E2 (PGE 2) possess tumor-promoting activity, and COX-2 is considered as a candidate for targeted cancer therapy. However, several randomized clinical trials using COX-2 inhibitors to treat advanced lung cancer have failed to improve survival indices. To employ a more effective therapeutic strategy to inhibit the COX-2-PGE 2 axis in tumors, it is necessary to revisit the mechanism underlying the protumor effect of COX-2-PGE 2.Patients and Methods: Immunohistochemistry was used to predict the expression and prognostic value of COX-2 in lung adenocarcinoma samples. The mRNAs or proteins expression of COX-2, pAKT1/2/3, pErk1/2 and pCREB were detected after different treatments by qPCR or Western blot. The impacts of PGE 2 and some inhibitors on cell proliferation and migration ability were verified by CCK-8 and transwell assays, respectively.Results: In this study, we first confirmed that COX-2 expression in tumor specimens is associated with the pathological stage of the disease. Next, using lung adenocarcinoma cell lines, we found that exogenous PGE 2 induces the expression of COX-2 at the mRNA and protein levels. Moreover, downregulation of COX-2 expression restrained PGE 2-induced cancer cell proliferation and migration. Mechanistic analysis revealed that PGE 2 stimulation activates the PKA-CREB and PI3K-AKT pathways. Downregulation of CREB expression abrogated PGE 2-induced COX-2 expression. Moreover, inhibition of PI3K-AKT signaling suppressed the activation of CREB and PGE 2-induced COX-2 expression. Specific inhibitors for PI3K and AKT suppressed COX-2 mRNA expression in ex vivo cultures of tumor specimens with PGE 2.Conclusion: Simultaneous targeting of COX-2 and PI3K-AKT effectively suppressed PGE 2-induced cell proliferation and migration and both acted in a synergistic manner. Targeting the COX-2-PGE 2 positive feedback loop may be therapeutically beneficial to lung adenocarcinoma.Keywords: PGE 2, COX-2, AKT, EP receptor, lung adenocarcinoma

Zhilai Lin, Jianguang Pan, Lei Chen, Xinhang Wang, Yuhua Chen Department of Respiratory Medicine, Fuzhou Pulmonary Hospital, Fujian Medical University, Fuzhou City, Fujian Province 350008, People’s Republic of ChinaCorrespondence: Zhilai Lin Email laizhil9899@163.comBackground: Although cisplatin is an effective chemotherapeutic drug that is commonly used for non-small-cell lung cancer (NSCLC) treatment, the drug resistance usually occurs during the long-term use of it. It is urgent to develop strategies to reduce the resistance of NSCLC cells to cisplatin.Methods: Cisplatin-resistant NSCLC cell lines (PC9/R and A549/R) were acquired through long-term exposure of PC9 and A549 cells to cisplatin. QRT-PCR analysis was performed to compare the expression of miR-140 between routine NSCLC cells and cisplatin-resistant NSCLC cells. CCK-8 assay was used to evaluate the effect of miR-140 on the sensitivity of PC9/R and A549/R to cisplatin. Western blot assay and luciferase reporter assay were used to confirm the regulation of miR-140 on SIRT1. Western blot and flow cytometry analysis were performed to evaluate the effect of miR-140 on the apoptosis pathway induced by cisplatin.Results: PC9/R and A549/R exhibited obviously lower sensitivity compared to their parental PC9 and A549 cells, respectively. Furthermore, PC9/R and A549/R cells expressed significantly lower levels of miR-140 compared to their parental PC9 and A549 cells, respectively. However, transfection with miR-140 mimics significantly resensitized the PC9/R and A549/R to cisplatin-induced cytotoxicity. In the mechanism research, we confirmed that SIRT1 was overexpressed and was targeted by miR-140 in PC9/R and A549/R. Furthermore, overexpression of SIRT1 was responsible for the resistance to cisplatin in PC9/R and A549/R cells. Transfection with miR-140 was able to inhibit the expression of SIRT1 and thus inhibited the SIRT1/ROS/JNK pathway. As a result, the PC9/R and A549/R cells restored the sensitivity to cisplatin-induced apoptosis.Conclusion: MiR-140 resensitizes cisplatin-resistant NSCLC cells to cisplatin treatment through the SIRT1/ROS/JNK pathway.Keywords: miR-140, cisplatin, NSCLC, SIRT1, ROS, JNK

Ye Cheng,1,* Hanzhi Sun,1,* Liangliang Wu,1,* Fan Wu,1 Weiwei Tang,1 Xiaowei Wang,2 Chengyu Lv1 1Department of General Surgery, Nanjing First Hospital, The Affiliated Nanjing Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 2Department of Medical Oncology, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huaian, Jiangsu, People’s Republic of China*These authors contributed equally to this work.Correspondence: Chengyu Lv; Xiaowei Wang Email lcy_1234@aliyun.com; wxw7352@sina.comBackground: Versican (VCAN), a significant protein of extracellular matrix (ECM), is capable of accumulating in tumor stroma and critically impacts malignant transforming process and tumor progressing process. Promoted VCAN expression was identified in numerous malignant tumors and showed relationships to cancer relapse and ineffective breast, prostate, and many other cancer types of patients. Nevertheless, the molecular capability and prognosis importance exhibited by VCAN are infrequently presented in gastric cancer (GC).Methods: According to 5 GC tissues and corresponding general tissues, mRNA expression profiles were taken here. VCAN expression in tissues was confirmed by quantitative reverse transcription polymerase reaction (qRT-PCR). The effect generated by VCAN expression on cell proliferating, invading and migrating processes was assessed in vitro with knockdown and overexpression strategies. Moreover, the relationships between immune response and VCAN expression in GC were assessed with the use of the software online.Results: There are 181 genes up-regulated and 530 genes down-regulated in GC. According to pathway study, the mentioned differently expressed mRNAs showed correlations with a number of vital physiological processes, cellular components, molecular functions and critical cancer signal pathways. VCAN was reported to be noticeably promoted in GC tissues and related to individual cancer age, race, and stages. VCAN was up-regulated in 16 GC tissues compared to adjacent non-tumorous tissue specimens via qRT-PCR. GC patients exhibiting higher VCAN expression had less post-progression survival (PPS), first progression (FP) and overall survival (OS). Experimental processes in vitro revealed VCAN knockdown hindered, proliferated, invaded, and migrated levels of GC cells, whereas overexpression of VCAN played the opposite effect. Immune factors may interact with VCAN mRNA in GC, and VCAN was found noticeably linked with regulatory T cells (Tregs).Conclusion: According to the mentioned results, VCAN critically impacts GC progression. Accordingly, VCAN is likely to be a potentially feasible prognosis marking element and a prominent cancer drug for GC patients.Keywords: VCAN, gastric cancer, prognosis, invasion, immune

Yan Liu,1,2,* Meng Gao,3,* Juan An,2,* Xin Wang,4 Yan Jia,4 Junfeng Xu,4 Jihai Zhu,5 Jiantao Cui,1 Wenmei Li,1 Rui Xing,1 Li Song,6 Kejia Liu,6 Yuqi He,4 Jianqiu Sheng,4 Shengmei Qi,3 Yuanming Pan,1,4 Youyong Lu1 1Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Beijing Cancer Hospital/Institute, School of Oncology, Peking University, Beijing, Haidian District 100142, People’s Republic of China; 2Department of Basic Medical Sciences, Medical College of Qinghai University, Xining City, Qinghai 810001, People’s Republic of China; 3OnkoRx Ltd. Beijing, Beijing, Haidian District 100085, People’s Republic of China; 4Department of Gastroenterology, The 7th Medical Center of Chinese PLA General Hospital, Beijing, Dongcheng District 100700, People’s Republic of China; 5Department of Cardiothoracic Surgery, The Affiliated Hospital of Qinghai University, Xining City, Qinghai 810001, People’s Republic of China; 6Yidu Cloud (Beijing) Technology Co., Ltd. 8F, Health Work, Beijing, Haidian District 100083, People’s Republic of China*These authors contributed equally to this workCorrespondence: Youyong Lu, MD, Ph.D.Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Beijing Cancer Hospital/Institute, School of Oncology, Peking University, Beijing 100142, People’s Republic of ChinaTel +86-10-88196765Fax +86-10-88122437Email youyonglu@hsc.pku.edu.cnBackground: Gastrin (GAST) is a well-known hormone regulating gastric biofunctions in the secretion of acid and maintaining its structural integrity. Furthermore, the dysregulation of GAST is also involved in the development of various forms of cancer. However, there are some limitations for illustrating the cellular regulation of GAST and its regulatory mechanisms in gastric malignant transformation and the potential epigenetic regulators systematically.Methods: We explored the role of GAST expression in gastric cancer (GC) and normal tissues with the clinical features and investigated the potential relationship between GAST and STAT3/MMP11 pathway by gain or loss of function analyses. Besides, based on our microRNA/mRNA expression profiles, miR-30a-3p was the potential epigenetic regulator and additional experiments were performed to identify the hypothesis.Results: Elevated GAST expression was frequently detected in GC and was associated with worse outcomes (p< 0.001). And we firstly demonstrated that GAST was negatively regulated by miR-30a-3p. Moreover, GAST induced GC cell proliferation, migration and invasion mediating STAT3/MMP11 pathway in this study.Conclusion: MiR-30a-3p was the promising suppressor gene through negatively regulating the expression of GAST, and dysregulation of GAST was a prognostic signature associated cell proliferation and metastasis through STAT3/MMP11 pathway in GC.Keywords: gastrin, proliferation, invasion, miR-30a-3p, STAT3/MMP11 pathway, gastric cancer

Yining Wu,1,* Jia Wei,1,* Wei Zhang,1,2 Mengxiao Xie,1,2 Xueying Wang,1 Jian Xu1,2 1Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People’s Republic of China; 2National Key Clinical Department of Laboratory Medicine, Nanjing 210029, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jian XuDepartment of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, People’s Republic of ChinaTel/ Fax +86 25 68303453Email xu_jian79@163.comPurpose: Lung cancer is a leading cause of cancer-related death, with lung adenocarcinoma (LUAD) representing the most common subtype. Recently, exosome-based biomarkers have provided new diagnostic approaches for malignancies. We aimed to identify specific exosomal microRNAs (miRNAs) as noninvasive biomarkers for LUAD.Patients and Methods: A total of 110 participants were enrolled and randomly divided into two sets: the discovery set (n=20) and the validation set (n=90). Exosomes were isolated from serum, and miRNAs were subsequently extracted. Candidate miRNAs (miR-21, miR-221-3p, miR-222-3p, miR-223, miR-638 and miR-1290) were detected by quantitative real-time PCR (qRT-PCR) in the discovery set. The upregulated miR-1290 was then selected for further analysis in the validation set along with three tumor markers (CEA, CYFRA21-1 and NSE). The diagnostic and prognostic value of exosomal miR-1290 were estimated through receiver-operating characteristic (ROC) and survival analysis.Results: Serum exosomal miR-1290 was significantly upregulated in LUAD patients compared to healthy controls (P< 0.001) and decreased after resection (P=0.0029). Its expression level was associated with tumor stage, tumor size, lymph node and distant metastasis (all P < 0.05). Exosomal miR-1290 had a higher diagnostic efficacy than CEA, CYFRA21-1 and NSE, with a sensitivity of 80.0% and specificity of 96.7% (AUC: 0.937, 95% CI: 0.890– 0.985; P< 0.001). Moreover, LUAD patients with a high level of exosomal miR-1290 had significantly poorer progression-free survival (PFS) than those with a low level of exosomal miR-1290 (mean PFS: 14 months vs 37 months, P< 0.001). Cox proportional hazards model analysis demonstrated that exosomal miR-1290 could be an independent risk factor for the prognosis of LUAD (HR=7.80, P=0.017).Conclusion: Serum exosomal miR-1290 could be a potential diagnostic and prognostic biomarker for LUAD.Keywords: lung adenocarcinoma, circulating miRNA, exosome, biomarker

Heyang Zhang,1 Lijun Zhang,1 Yan Li,1 Hongcang Gu,2 Xiaoxue Wang1 1Department of Hematology, The First Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of China; 2Broad Institute of MIT and Harvard, Cambridge, MA, USACorrespondence: Xiaoxue Wang; Hongcang Gu Email liang195691@163.com; gu_hongcang@hotmail.comObjective: To investigate the characteristics of hematological malignancies in patients with the SET-CAN fusion gene and provide a literature review.Methods: We retrospectively analyzed the clinical data of three cases of acute leukemia and myeloid neoplasms harboring the SET-CAN fusion gene who were treated at our hospital. Their clinical manifestations, pathological results and treatment strategies were investigated.Results: The three cases were diagnosed with T-cell acute lymphoblastic leukemia (T-ALL), acute myeloid leukemia (AML) and myeloid sarcoma (MS), respectively. Karyotype analyses identified a normal result in all three patients. Subsequently, we confirmed del(9q34) utilizing FISH analysis. Mutation of the BRAF gene was detected in case 1, while mutations in PHF6 and BCOR were detected in case 2, which have not been officially reported in patients with SET-CAN fusions. Finally, relevant literature focusing on adult patients with hematological malignancies harboring the SET-CAN fusion gene were summarized.Conclusion: Adult patients with the SET-CAN fusion gene were rare among cases of hematological malignancies. There was a large degree of heterogeneity between different patients. Notably, some patients remained sensitive to chemotherapy. Overall prognosis may be related to the type of disease and other cytogenetic abnormalities. Systemic cytogenetic and molecular studies are needed to make accurate diagnoses. Additional cases need to be accumulated and summarized to better understand these diseases.Keywords: T-lymphoblastic lymphoma/leukemia, acute myeloid leukemia, myeloid sarcoma, SET-CAN, ASCT, prognosis