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Zhao X, Xie T, Zhao W, Cai W, Su X. Onco Targets Ther. 2019;12:1965–1977. We, the Editor and Publisher of the journal OncoTargets and Therapy are retracting the published article. Following publication of the article, concerns were raised regarding the duplication of images from Figure 1 with images from unrelated articles. Specifically, The images for Figure 1C, Patient 2 and Patient 3, ANT, have been duplicated with the images for Figure 1D, Clinical stage I, 200X and Normal, 400X, respectively from Zhao X, Xie T, Dai T, et al. CHP2 Promotes Cell Proliferation in Breast Cancer via Suppression of FOXO3a. Mol Cancer Res. 2018;16(10):1512–1522. https://doi.org/10.1158/1541-7786.MCR-18-0157. The image for Figure 1D, Clinical stage III, 200x, has been duplicated with the image for Figure 1C, Tumor, 200X, from Wang X, Lin C, Zhao X, et al. Acylglycerol kinase promotes cell proliferation and tumorigenicity in breast cancer via suppression of the FOXO1 transcription factor. Mol Cancer. 2014;13:106. https://doi.org/10.1186/1476-4598-13-106. The images for Figure 2C, ZR-75-30, siMMSET and Figure 4C, ZR-75-30, siMMSET+pcDNA3.1, have been duplicated. The images for Figure 2C, MDA-MB-231, siCon and Figure 4C, ZR-75-30, siMMSET, have been duplicated. The images for Figure 3B, MDA-MB-231, siCon and Figure 4E, MDA-MB-231, siMMSET+MMSET, have been duplicated. The corresponding author did not respond to our queries and was unable to provide a satisfactory explanation for how the images came to be duplicated or provide satisfactory original data for the study. As verifying the validity of published work is core to the integrity of the scholarly record, the Publisher and Editor requested to retract the article and the corresponding author was notified of this. We have been informed in our decision-making by our editorial policies and COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Huixian Zhang,1– 3 Wencheng Zhao,1,2 Xingya Li,3 Yayi He1,2 1Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, 200433, People’s Republic of China; 2Tongji University, Shanghai, 200433, People’s Republic of China; 3Department of Medical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou City, Henan Province, 450052, People’s Republic of ChinaCorrespondence: Yayi HeDepartment of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, 200433, People’s Republic of ChinaTel +86-13818828623Email 2250601@qq.comXingya LiDepartment of Medical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou City, Henan Province, 450052 Tel +86-13838253946Email fcclixy1@zzu.edu.cnAbstract: Checkpoint-based immunotherapies, such as programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) inhibitors, have shown promising clinical outcomes in many types of cancers. Unfortunately, the response rate of immune checkpoint inhibitors is low. It is very important to discover novel therapeutic targets and prognostic biomarkers. Cholesterol metabolism has been demonstrated to be related to the occurrence and development of a variety of tumors and may provide a new breakthrough in the development of immunotherapy. First of all, cholesterol metabolism in the tumor microenvironment affects the function of tumor-infiltrating immune cells. In addition, intracellular cholesterol homeostasis is an important regulator of immune cell function. Furthermore, drugs that act on cholesterol metabolism affect the efficacy of immunotherapy. What is more, peripheral blood cholesterol level can be a biomarker to predict the efficacy of immunotherapy. In this review, we aimed to explore the potential role of cholesterol metabolism on immunotherapy. By summarizing the major findings of recent preclinical and clinical studies on cholesterol metabolism in immunotherapy, we suggested that cholesterol metabolism could be a potential therapeutic target and a prognostic biomarker for immunotherapy.Keywords: cholesterol metabolism, immunotherapy, immune cell, therapeutic target, biomarker

Hao Wang,1,2 Shanhao Chen,1 Die Meng,1,2 Chunyan Wu,3 Junjie Zhu,4 Minlin Jiang,1,2 Jing Ning,1,2 Shengyu Wu,1,2 Lijia Wu,5 Jingjie Li,5 Bin Chen,1 Sha Zhao,1 Wei Li,1 Jia Yu,1,2 Qiyu Fang,1,2 Jun Zhu,1,2 Wencheng Zhao,1,2 Yayi He,1 Caicun Zhou1 1Department of Medical Oncology, Shanghai Pulmonary Hospital, Shanghai, 200433, People’s Republic of China; 2Medical School, Tongji University, Shanghai, 200433, People’s Republic of China; 3Pathology Department, Shanghai Pulmonary Hospital, Shanghai, 200433, People’s Republic of China; 4Surgery Department, Shanghai Pulmonary Hospital, Shanghai, 200433, People’s Republic of China; 5Genecast Biotechnology Co., Ltd, Wuxi City, Jiangsu, 214104, People’s Republic of ChinaCorrespondence: Yayi He; Caicun ZhouDepartment of Medical Oncology, Shanghai Pulmonary Hospital, No. 507 Zhengmin Road, Shanghai, People’s Republic of ChinaTel +86 13818828623; Tel +86 13818828623Email 2250601@qq.com; caicunzhoudr@126.comIntroduction: Nowadays, immune checkpoint blockades (ICBs) have been extensively applied in non-small cell lung cancer (NSCLC) treatment. However, the outcome of anti-program death-1/program death ligand-1 (anti-PD-1/PD-L1) therapy is not satisfying in EGFR-mutant lung adenocarcinoma (LUAD) patients and its exact mechanisms have not been fully understood. Since tumor mutation burden (TMB) and tumor immune phenotype had been thought as potential predictors for efficacy of ICBs, we further studied the TMB and immune phenotype in LUAD patients to explore potential mechanisms for poor efficacy of ICBs in EGFR positive mutated patients and to find possible factors that could impact the tumor immune phenotype which might uncover some new therapeutic strategies or combination therapies.Methods: We enrolled 223 LUAD patients who underwent surgery in our hospital. We evaluated TMB through targeted panel sequencing. The tumor immune phenotype, which could be divided into non-inflamed, intermediate and inflamed, was determined through immunohistochemistry using formalin-fixed paraffin-embedded samples. Enumeration data were analyzed by Chi-square test or Fisher exact test and shown as number (proportion). Logistic regression model was employed for univariate and multivariate analysis of the association between TMB levels and clinical characteristics.Results: The median TMB level was 4.0445 mutations/Mb. Multivariate analysis showed the TMB level was significantly associated with age (P=0.026), gender (P=0.041) and EGFR mutation status (P=0.015), and in EGFR-mutant patients we found a lower proportion of patients with mutated KRAS and BRCA2. Furthermore, we found patients with or without metastatic lesions would have different immune phenotype (P=0.007). And the mutational frequencies of ALK, CDKN2A, MAP2K1, IDH2 and PTEN were significantly different among three immune phenotypes.Conclusion: Low TMB level could be the reason for the poor efficacy of ICBs in patients having EGFR mutation. And mutational frequencies of KRAS and BRCA2 were lower in EGFR-mutant patients. Furthermore, ALK, CDKN2A, MAP2K1, IDH2 and PTEN might involve in the formation of immune phenotypes.Keywords: lung adenocarcinoma, EGFR mutation, tumor mutation burden, immune phenotype, immune checkpoint blockade

Hao Wang,1,2 Die Meng,1,2 Haoyue Guo,1,2 Chenglong Sun,1,2 Peixin Chen,1,2 Minlin Jiang,1,2 Yi Xu,1,2 Jia Yu,1,2 Qiyu Fang,1,2 Jun Zhu,1,2 Wencheng Zhao,1,2 Shengyu Wu,1,2 Sha Zhao,1 Wei Li,1 Bin Chen,1 Lei Wang,1 Yayi He1 1Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, 200433, People’s Republic of China; 2Tongji University, School of Medicine, Shanghai, 200433, People’s Republic of ChinaCorrespondence: Yayi HeDepartment of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, No 507 Zhengmin Road, Shanghai, 200433, People’s Republic of ChinaTel +86 13818828623Email 2250601@qq.comAbstract: Single-cell sequencing (SCS) which has an unprecedentedly high resolution is an advanced technique for cancer research. Lung cancer still has a high mortality and morbidity. For further understanding the lung cancer, SCS is also been applied to lung cancer research to investigate its heterogeneity, metastasis, drug resistance, tumor microenvironment and many other issues. In this review, we summarized lung cancer research using SCS and their research achievements.Keywords: single-cell sequencing, lung cancer, intratumoral heterogeneity, tumor microenvironment, lung cancer therapy

Cuiyun Su,1 Ya Jiang,2 Wei Jiang,1 Huilin Wang,1 Sisi Liu,2 Yang Shao,2 Wenhua Zhao,1 Ruiling Ning,1 Qitao Yu1 1Department of Respiratory Oncology, Guangxi Medical University Affiliated Tumor Hospital, Nanning, China; 2Department of Research and Development, Nanjing Geneseeq Technology Inc, Nanjing, Jiangsu, ChinaCorrespondence: Qitao Yu Email yqt133@126.comAbstract: Non-small cell lung cancer (NSCLC) patients with anaplastic lymphoma kinase (ALK) rearrangement benefit from treatment with ALK inhibitors. Therefore, the identification of druggable ALK fusions is necessary for NSCLC treatment. More than 90 fusion partners of ALK have been reported in NSCLC patients, but the striatin gene (STRN)-ALK fusion has rarely been reported. Moreover, the response of STRN-ALK fusion patients treated with ALK inhibitors remains to be explored. A 64-year-old Chinese male with no history of smoking or alcohol consumption was diagnosed as stage IVB lung adenocarcinoma (LADC) (cT4N3M1c) in October 2018. Next-generation sequencing (NGS) targeting 425 cancer-related genes was performed on the plasma and supernatant of pleural effusion samples and revealed an STRN-ALK fusion. The patient received alectinib (600 mg, twice daily) as the first-line treatment with an excellent response exceeding 19 months. This is the first report of a NSCLC patient harboring an STRN-ALK fusion and exhibiting an excellent response to alectinib treatment. This case provides valuable information for therapeutic decision-making of patients with STRN-ALK fusions. Furthermore, this case also highlighted the advantage of performing targeted NGS on circulating tumor DNA for the identification and analysis of rare, druggable genomic alterations.Keywords: lung adenocarcinoma, STRN-ALK fusion, ctDNA, alectinib, targeted NGS

Weifeng Zhao,1 Zhoufeng Huang,1,2 Huimin Liu,1 Chaojie Wang1 1Department of Oncology, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, Zhengzhou City, Henan Province 450003, People’s Republic of China; 2Institute of Hematology, Henan Provincial People’s Hospital, Zhengzhou City, Henan Province 450003, People’s Republic of ChinaCorrespondence: Chaojie WangDepartment of Oncology, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, No. 7 Weiwu Road, Jinshui District, Zhengzhou City, Henan Province 450003, People’s Republic of ChinaEmail chaojiewangoncolog@163.comBackground: Esophageal cancer is one of the most frequent cancers with a higher mortality worldwide. Although many long non-coding RNAs (LncRNAs) are reported to play important roles in the progression of esophageal cancer, the function of lncRNA GIHCG in esophageal cancer remains unclear.Methods: The expression of GIHCG in esophageal cancer tissues and cancer cell lines was detected by qRT-PCR. Cell proliferation was evaluated by Cell Counting Kit-8 (CCK-8) assay, EdU staining assay and colony formation assay. Cell invasion and migration were measured by transwell assay. Cell apoptosis was detected by a flow cytometer. Luciferase reporter assay and RIP assay were used to determine the interaction between GIHCG and miR-29b-3p, and their subsequent regulation of anoctamin 1 (ANO1). The expression of ANO1 in esophageal cancer tissues and cell lines was detected by Western blot. The effect of GIHCG/miR-29b-3p in tumor formation was assessed by the xenograft nude mice model in vivo.Results: GIHCG was significantly upregulated in esophageal cancer tissues and relevant cancer cell lines. Downregulation of GIHCG significantly inhibited the growth, colony formation, invasion, migration and induced apoptosis of esophageal cancer cells in vitro. Bioinformatic analysis and RIP assay determined that GIHCG was a sponge of miR-29b-3p, and ANO1 was a direct target of miR-29b-3p. Moreover, functional experiments showed that GIHCG upregulated ANO1 expression by directly sponging miR-29b-3p. Furthermore, in vivo experiment revealed that knockdown of GIHCG significantly inhibited tumor growth in nude mice.Conclusion: Our study revealed that lncRNA GIHCG promoted the progression of esophageal cancer by targeting the miR-29b-3p/ANO1 axis, suggesting that GIHCG might be a novel therapeutic target for esophageal cancer.Keywords: esophageal cancer, GIHCG, miR-29b-3p, ANO1, tumorigenesis

Binbin Wang,* Shuxia Yang,* Wei Zhao Department of Hepatology, Qingdao Sixth People’s Hospital, Qingdao, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei ZhaoDepartment of Hepatology, Qingdao Sixth People’s Hospital, No. 9 Fushun Road, Qingdao 266000, People’s Republic of ChinaTel/ Fax +861057830131Email zhaowqdsph@tom.comBackground: Hepatocellular carcinoma (HCC) is prevalent throughout the world. The aim of this study is to explore new long non-coding RNAs (lncRNAs) associated with hepatocellular carcinoma and detect their expression levels in hepatocellular carcinoma cell lines and tissues. These results will provide new clues on further function and biomarker studies of HCC-related lncRNAs.Patients and Methods: All patients were diagnosed as HCC between 30th, March, 2015 and 30th, July, 2018. LncRNA human gene expression microarray was applied to the profiling of lncRNAs in four cancerous tissues and the paired paracancerous tissues.Results: We retrospectively reviewed 63 patients with primary HCC who underwent a curative liver resection at the Department of Hepatology, Qingdao Sixth People’s Hospital. The expression level of lncRNA NRAD1 and LINC00152 was detected by real-time PCR. Prognostic factors were evaluated using Kaplan–Meier curves and Cox proportional hazards models. By microarray profiling of lncRNAs, 256 lncRNAs were found to be differentially expressed, including 162 upregulated and 94 downregulated (P< 0.05, fold change> 2). Two candidate lncRNAs were determined as the targets in this study, which were NRAD1 (upregulated by 6.35 fold), LINC00152 (upregulated by 4.53 fold). NRAD1 and LINC00152 were downregulated in the normal liver cell lines Chang liver, HL7702, THLE-2, THLE-3, FL62891 and AML12, which were significantly lower than HCC cell lines SMMC-7721, Hep3B, HuH7, MHCC-97H, HCC-LM and SK-Hep-1 (P< 0.05). Overexpression of lncRNA NRAD1 and LINC00152 was associated with decreasing OS rates, respectively (P=0.0263 and P=0.0285). Meanwhile, overexpression of NRAD1 and LINC00152 was associated with decreasing PFS rates, respectively (P=0.0174 and P=0.0041). After adjusting for competing risk factors, we identified that microvascular invasion (P=0.014), tumor size (P=0.026), lncRNA NRAD1 (P=0.001) and LINC00152P9 (P=0.036) expression levels were independent prognostic factors associated with prognosis of patients with HCC.Conclusion: We found lncRNA NRAD1 and LINC00152 expressed significantly higher in HCC tissues compared with non-tumorous tissues. Overexpression of lncRNA NRAD1 and LINC00152 were independent risk factors associated with the prognosis of patients with HCC.Keywords: long non-coding RNA, HCC, NRAD1, LINC00152

Xunlei Zhang,1,* Wenjing Zhao,2,* Xin Chen,3,* Min Zhao,4 Xue Qi,5 Guoxing Li,3 Aiguo Shen,2 Lei Yang1 1Department of Oncology, Affiliated Tumor Hospital of Nantong University, Nantong Jiangsu, People’s Republic of China; 2Cancer Research Center, Affiliated Tumor Hospital of Nantong University, Nantong Jiangsu, People’s Republic of China; 3Department of General Surgery, Affiliated Tumor Hospital of Nantong University, Nantong Jiangsu, People’s Republic of China; 4Department of Pathology, Affiliated Tumor Hospital of Nantong University, Nantong Jiangsu, People’s Republic of China; 5Department of Oncology, Nantong Liangchun Hospital of Traditional Chinese Medicine, Nantong, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lei Yang Email leiyang.53@163.comAiguo Shen Email 529781393@qq.comBackground: Inflammation and nutrition are important causes contributing to the progression and poor survival of gastric cancer (GC). The objective of this study is to investigate the prognostic significance of the preoperative fibrinogen-to-pre-albumin ratio (FPR) and the prognostic nutritional index (PNI) in GC patients who have undergone gastrectomy.Methods: A total of 274 patients with resected pathological GC from January 2007 to December 2013 were enrolled in this retrospective study. Survival analysis was performed using Kaplan–Meier and log rank tests. Univariate and multivariate analyses were established to identify independent prognostic factors of 5-year survival. A predictive nomogram was used to predict prognosis of overall survival (OS), and its accuracy was determined by Harrell’s concordance index (C index).Results: A high preoperative FPR-PNI score was significantly correlated with age, bigger tumor size, more lymphatic metastases and advanced TNM stage. Univariate analysis revealed that the GC patients with high FPR, low PNI and high FPR-PNI scores had shorter survival time. Multivariate analysis showed that FPR-PNI was an independent prognostic factor for OS in GC patients, especially in elderly patients. In the sub-analysis by age, the FPR-PNI score could significantly increase the accuracy of prognosis compared with the FPR and PNI alone in elderly GC patients.Conclusion: The preoperative FPR-PNI score is an effective independent prognostic index for GC patients after surgery, especially in elderly patients.Keywords: gastric cancer, prognostic nutritional index, fibrinogen-to-pre-albumin ratio, FPR-PNI, prognosis

Rui Chen, Yan Chen, Weiqing Zhao, Cheng Fang, Wenjie Zhou, Xin Yang, Mei Ji Department of Oncology, The Third Affiliated Hospital of Soochow University, The First People’s Hospital of Changzhou, Changzhou 213003, People’s Republic of ChinaCorrespondence: Xin Yang; Mei Ji Email yangxindoctor@163.com; zlkjimei@163.comAbstract: Malignant solid tumors are the leading cause of death in humans, and epigenetic regulation plays a significant role in studying the mechanism of human solid tumors. Recently, histone lysine methylation has been demonstrated to be involved in the development of human solid tumors due to its epigenetic stability and some other advantages. The 90-kb protein methyltransferase nuclear receptor SET domain-containing 2 (NSD2) is a member of nuclear receptor SET domain-containing (NSD) protein lysine methyltransferase (KMT) family, which can cause epigenomic aberrations via altering the methylation states. Studies have shown that NSD2 is frequently over-expressed in multiple types of aggressive solid tumors, including breast cancer, renal cancer, prostate cancer, cervical cancer, and osteosarcoma, and such up-regulation has been linked to poor prognosis and recurrence. Further studies have identified that over-expression of NSD2 promotes cell proliferation, migration, invasion, and epithelial–mesenchymal transformation (EMT), suggesting its potential oncogenic role in solid tumors. Moreover, Gene Expression Profiling Interactive Analysis (GEPIA) was searched for validation of prognostic value of NSD2 in human solid tumors. However, the underlying specific mechanism remains unclear. In our present work, we summarized the latest advances in NSD2 expression and clinical applications in solid tumors, and our findings provided valuable insights into the targeted therapeutic regimens of solid tumors.Keywords: NSD2, proliferation, migration, invasion, EMT, oncogene

Weigang Zhao,1,* Tangbing Chen,2,* Yonghong Zhao1 1Department of Thoracic Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200030, People’s Republic of China; 2Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yonghong ZhaoDepartment of Thoracic Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, 600 Yishanlu Road, Xuhui District, Shanghai 200030, People’s Republic of ChinaEmail yonghong_zhao@yeah.netIntroduction: Non-small cell lung cancer (NSCLC) is a deadly cancer type worldwide and the main sub-type of lung cancer. Cancer susceptibility candidate-9 (CASC9) was reported to be a key player in cancer progression. However, its function and underlying mechanism in NSCLC remain unclear.Materials and Methods: Expression level of CASC9 in NSCLC tissues and cells was measured with RT-qPCR. Biological roles of CASC9 in NSCLC were analyzed with a series of in vitro experiments. Potential mechanisms of CASC9 in NSCLC were analyzed by predicting and validating the possible targets of CASC9 in NSCLC.Results: In this study, we found CASC9 expression was upregulated in NSCLC tissues and cell lines. High CASC9 expression was identified as a predictor for poorer overall survival of NSCLC patients. Furthermore, functional assays showed CASC9 knockdown suppressed NSCLC cell proliferation, migration, and invasion, while CASC9 overexpression caused opposite effects. We also found microRNA-335-3p (miR-335-3p) could act as a target of CASC9 in NSCLC and the inhibition effect of CASC9 knockdown on NSCLC progression required the activity of miR-335-3p. In addition, we identified S100 calcium-binding protein A14 (S100A14) acts as a target of miR-335-3p.Discussion: Taken together, our study suggested CASC9 could promote NSCLC progression via miR-335-3p/S100A14 axis. The CASC9/miR-335-3p/S100A14 regulatory triplets identified in this work might provide new therapeutic strategies for NSCLC treatment.Keywords: non-small cell lung cancer, CASC9, miR-335-3p, S100A14, ceRNA

Yue Zhao,1,2,* Ya-qi Yu,1,* Song You,3 Chang-mao Zhang,4 Liang Wu,5 Wenxiu Zhao,1 Xiao-min Wang1 1Department of Hepatobiliary Surgery, Zhongshan Hospital, Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen, Fujian 361004, People’s Republic of China; 2Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich 81377, Germany; 3Mengchao Hepatobiliary Hospital of Fujian Medical University, The Liver Center of Fujian Province, Fujian Medical University, Fuzhou 350025, People’s Republic of China; 4Faculty of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 5Department of Nephrology, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiao-min WangDepartment of Hepatobiliary Surgery, Zhongshan Hospital, Xiamen University, Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Xiamen, Fujian 361004, People’s Republic of ChinaEmail wxm2203@xmu.edu.cnPurpose: Accumulating studies have explored the potential diagnostic value of lncRNA MALAT1 in various cancers. However, there are still inconsistent results in diagnostic accuracy and reliability in individual studies. The aim of this pooled study was to summarize the overall diagnostic capacity of lncRNA MALAT1 in cancer detection and diagnosis.Methods: Eligible studies satisfying the inclusion criteria were screened and selected from the online database. All statistical analyses were performed using Stata 14.0.Results: A total of 17 eligible studies were included in this pooled analysis, with 1777 cases and 1478 controls. The overall results were shown as follows: sensitivity, 0.74 (95% CI=0.65– 0.81), specificity, 0.79 (95% CI=0.73– 0.84), positive likelihood ratio (PLR), 3.48 (95% CI=2.79– 4.32), negative likelihood, 0.33 (95% CI=0.25– 0.44), diagnostic score, 2.34 (95% CI=1.99– 2.69), diagnostic odds ratio, 10.41 (95% CI=7.33– 14.78) and area under the curve, 0.83 (95% CI=0.80– 0.86). Deeks’ funnel plot asymmetry test (p = 0.66) suggested no potential publication bias.Conclusion: All these results indicate that lncRNA MALAT1 achieves a relatively moderate accuracy in cancer detection and diagnosis, and could serve as a diagnostic biomarker for cancers.Keywords: lncRNA, MALAT1, cancer, pooled analysis, detection, diagnosis

Xiaoli Wang,1 Liming Liu,2 Wenfei Zhao,3 Qingyan Li,4 Guangsheng Wang,5 Huahui Li6 1Department of Clinical Laboratory, Jinan City People’s Hospital, Jinan People’s Hospital Affiliated to Shandong First Medical University, Jinan 271199, People’s Republic of China; 2Department of Otorhinolaryngology, Juye County Hospital of TCM, Heze 274900, People’s Republic of China; 3Department of Comprehensive Oncology Therapy, Qingdao Central Hospital, Qingdao University, Qingdao 266043, People’s Republic of China; 4Department of Clinical Laboratory, The People’s Hospital of Zhangqiu Area, Jinan 250200, People’s Republic of China; 5Department of Neurology, The People’s Hospital of Zhangqiu Area, Jinan 250200, People’s Republic of China; 6Department of Clinical Laboratory, Qingdao Municipal Hospital, Qingdao 266071, People’s Republic of ChinaCorrespondence: Huahui Li Email jigcgk24849@163.comObjective: Laryngeal cancer is a common malignant tumor in the ENT, of which laryngeal squamous cell carcinoma (LSCC) accounts for more than 90% of laryngeal cancer. The purpose of this study is to investigate the regulatory mechanism of lncRNA SNHG16 in LSCC.Materials and Methods: Real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to measure mRNA expression. Cell Counting Kit (CCK-8), Transwell and luciferase reporter assays, flow cytometric analysis and Western blot analysis were used to investigate the function of lncRNA SNHG16 in LSCC.Results: SNHG16 expression was increased in LSCC tissues and cells. The abnormal expression of SNHG16 was associated with clinical stage and lymph node metastasis in LSCC patients. In addition, knockdown of SNHG16 restrained cell proliferation, migration and invasion in LSCC. More importantly, SNHG16 acted as a competitive endogenous RNA in LSCC and regulated FOXP4 expression by making miR-877-5p sponge. Further, SNHG16 promoted LSCC progression by interacting with miR-877-5p and FOXP4.Conclusion: LncRNA SNHG16 promotes the progression of LSCC by sponging miR-877-5p and upregulating FOXP4.Keywords: SNHG16, laryngeal squamous cell carcinoma, miR-877-5p, FOXP4

Xiaofang Shen,1,* Wei Zhao,1,* Yumei Zhang,2 Bin Liang2 1Department of Obstetrics-Gynecology, Dongying City People’s Hospital, Dongying City, Shandong Province 257091, People’s Republic of China; 2Department of Obstetrics-Gynecology, Dongying City Dongying District People’s Hospital, Dongying City, Shandong Province 257000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaofang ShenDepartment of Obstetrics-Gynecology, Dongying City People’s Hospital, No. 317, Nanyi Road, Dongying District, Dongying City, Shandong Province 257091, People’s Republic of ChinaTel +86-13780757608Email shenxiaofang142@163.comBackground: This study aimed to investigate the regulatory role of lncRNA-NEAT1 on cervical cancer (CC) and the underlying molecular mechanisms.Methods: The expression of lncRNA-NEAT1 and miR-124 was detected in CC tissues and cells (HeLa and SiHa cells) by qRT-RCR. The relation between lncRNA-NEAT1 expression and clinical parameters of CC patients was explored. The cell migration and invasion were detected by wound healing assay and transwell assay. The cell proliferation was detected by CCK-8 and anchorage-independent colony assay. The targeting relation between miR-124 and lncRNA-NEAT1 was predicted by TargetScan and identified by dual luciferase reporter gene and RNA pull-down assay. The expression of metastasis- (MMP-2 and MMP), EMT- (E-cadherin, N-cadherin and Vimentin), and NF-κB pathway-related factors (NF-κB p65, p-NF-κB p65 and IκBα) was detected by Western blot.Results: The expression of lncRNA-NEAT1 was upregulated in CC tissues and cells and positively correlated with TNM stage and lymph node metastasis. Overexpression of lncRNA-NEAT1 promoted the proliferation, migration and invasion, influenced the expression of EMT markers, and activated NF-κB pathway in HeLa and SiHa cells. Silencing of lncRNA-NEAT1 exhibited opposite effects on HeLa and SiHa cells. LncRNA-NEAT1 could negatively regulate its target miR-124. MiR-124 reversed the effects of lncRNA-NEAT1 on the migration, invasion, EMT and NF-κB pathway of HeLa cells.Conclusion: LncRNA-NEAT1 promoted the migration and invasion of CC cells via regulating miR-124/NF-κB pathway.Keywords: cervical cancer, lncRNA-NEAT1, migration, invasion, miR-124/NF-κB pathway

Yue Bai,1 Lili Lang,2 Wentao Zhao,1 Rong Niu1 1Department One of Thoracic Surgery, Gansu Provincial Cancer Hospital, Gansu, People’s Republic of China; 2Department of Radiology, Gansu Provincial Cancer Hospital, Gansu, People’s Republic of ChinaCorrespondence: Rong NiuDepartment One of Thoracic Surgery, Gansu Provincial Cancer Hospital, No.2, Little West Lake, East Street, Qilihe District, Lanzhou City, Gansu Province, People’s Republic of ChinaTel +86-13893604704Email rhjren12@sina.comObjective: Our present study aimed to further investigate the molecular basis of long non-coding RNA homeobox A11 antisense (HOXA11-AS) in the tumorigenesis of non-small cell lung cancer (NSCLC).Methods: HOXA11-AS, microRNA-148a-3p (miR-148a-3p), and DNA methyltransferase 1 (DNMT1) mRNA levels were measured by RT-qPCR assay. DNMT1 protein level was determined by Western blot assay. Cell proliferative capacity and apoptotic rate were determined by CCK-8 assay and flow cytometry analysis, respectively. The relationships of HOXA11-AS, miR-148a-3p, and DNMT1 were tested through bioinformatics analysis, luciferase assay, and RNA pull down assay. Mouse xenograft models of NSCLC were established to examine the biological function of HOXA11-AS in vivo.Results: HOXA11-AS expression was notably upregulated and miR-148a-3p expression was conspicuously downregulated in NSCLC tissues and cells. HOXA11-AS knockdown curbed NSCLC cell proliferation and promoted cell apoptosis through directly increasing miR-148a-3p expression. Moreover, miR-148a-3p overexpression suppressed NSCLC cell proliferation and induced cell apoptosis. HOXA11-AS functioned as a competing endogenous RNA (ceRNA) of miR-148a-3p to increase DNMT1 expression in NSCLC cells. And, DNMT1 upregulation weakened the influence of HOXA11-AS1 loss on NSCLC cell proliferation and apoptosis. Additionally, HOXA11-AS knockdown suppressed NSCLC xenograft growth by upregulating miR-148a-3p and downregulating DNMT1 in vivo.Conclusion: HOXA11-AS facilitated NSCLC tumorigenesis through miR-148a-3p/DNMT1 axis in vitro and in vivo, deepening our understanding of the molecular basis of HOXA11-AS in the development of NSCLC.Keywords: non-small cell lung cancer, tumorigenesis, HOXA11-AS, miR-148a-3p, DNMT1

Jing Wang,1,* Ning Wang,1,* Wei-dong Zhao,2 Li-xian Zhao,2 Yong-guang Jing,3 Li-jie Yang,2 Jie He,2 Jun Li1 1Department of Surgery, School of Clinical Medicine, Dali University, Dali, Yunnan 671000, People’s Republic of China; 2The First Affiliated Hospital of Dali University, Dali, Yunnan 671000, People’s Republic of China; 3Department of Human Anatomy, School of Basic Medical Sciences, Dali University, Dali, Yunnan 671000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jun Li; Jing WangDepartment of Surgery, School of Clinical Medicine, Dali University, Xue-Ren Road, Xia Guang District, Dali, Yunnan 671000, People’s Republic of ChinaEmail Lijun6408@163.com; jingwang163@hotmail.comBackground: The abnormal regulation on the expression of lncRNAs had been linked to multiple kinds of cancers, including lung adenocarcinoma.Methods: In this study, we carried out RNA-Seq on the three tumors and their paired normal samples from Chinese patients with lung adenocarcinoma. All the transcripts were de novo assembled, among which all the possible lncRNAs were predicted by tools including PLEK, CNCI, CPC, Blastp, hmmscan, and so forth. Their expression levels, altogether with the annotated mRNAs, were quantified. The weighted correlation network analysis and analysis of differential expression were carried out to explain the biological function of these novel lncRNAs.Results: The weighted correlation network analysis showed that the lncRNAs, which were highly correlated with protein-coding genes, participated in various pathways, including PI3K kinase pathways. These lncRNAs were important regulators in biological processes. Next, the differentially expressed lncRNAs were identified, including four known lncRNAs and one novel lncRNA (XLOC_009190). The cis-regulation of this novel lncRNA might act on MGST1, which protected cells by conjugation and glutathione peroxidase functions. The trans-regulation of this lncRNA was investigated by its correlated mRNAs. The results showed that it possibly played a role in transmembrane receptors like G protein-coupled receptors and potassium channels.Conclusion: We proposed the potential biological function of XLOC_009190, but further experiments are needed to elucidate its roles and its potential to be the therapeutic target.Keywords: lung adenocarcinoma, RNA-Seq, lncRNAs, de novo assembly

Cao Zhang,* Haiquan Qian,* Ke Liu, Wei Zhao, Lei Wang The Department of Gastrointestinal Surgery, General Hospital of Ningxia Medical University, Yinchuan City, The Ningxia Hui Autonomous Region, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lei WangThe Department of Gastrointestinal surgery, General Hospital of Ningxia Medical University, No.804, Shengli South Road, Yinchuan City, The Ningxia Hui Autonomous Region 750004, People’s Republic of ChinaEmail wangleinmu@163.comBackground: Gastric cancer (GC) is one of the most common cancers and the second leading cause of cancer-related death worldwide. Long noncoding RNAs (lncRNAs) are associated with GC development and progression. However, the functional roles and underlying mechanism of LINC01433 on GC progression remain elusive.Methods: Firstly, the expression of LINC01433 was examined in 76 pairs of primary GC and corresponding adjacent non-tumorous tissues. Next, overexpression and knockdown experiments were conducted in GC cells to explore the effect of LINC01433 on the malignant behaviors of GC cells. Then, the interaction between LINC01433 and YAP was detected by RNA immunoprecipitation (RIP) and RNA pull-down assays.Results: We found that LINC01433 was significantly upregulated in GC tissues and cell lines and correlated with poor prognosis. Through gain- and loss-of-function experiments, we demonstrated that LINC01433 promoted proliferation, migration, invasion and chemotherapy resistance in GC cells. Further mechanistic investigation revealed that LINC01433 could stabilize oncoprotein YAP through enhancing the interaction between deubiquitinase USP9X and YAP. LINC01433 decreased the phosphorylation of YAP via suppressing YAP-LATS1 association. Intriguingly, YAP directly bound to LINC01433 promoter region and activated its transcription. Thus, LINC01433 and YAP formed a positive feedback loop.Conclusion: Collectively, our study demonstrates that the positive feedback loop between LINC01433 and YAP promotes GC progression, and implies that the LINC01433-YAP feedback loop may be a promising therapeutic target for GC treatment.Keywords: protein stability, USP9X, YAP, LATS1

Sun M, Chen Z, Tan S, Liu C, Zhao W. Onco Targets Ther. 2018;11:1961–1971. The Editor and Publisher of OncoTargets and Therapy wish to retract the published article. Concerns were raised regarding alleged image duplication in Figure 4C. Specifically: Figure 4C, panel BC has been duplicated with Figure 4C, panel NC with the image having been flipped and rotated. The authors responded to our queries but were unable to provide a satisfactory explanation for the alleged image duplication or adequate raw data for their study. The findings of the article were deemed invalid and the Editor requested for the article to be retracted. Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”. This retraction relates to this paper

Xuefeng Gu,1,2,* Yuan Mao,3,* Chuanbing Shi,4 Wei Ye,2 Ning Hou,5 Li Xu,5 Yan Chen,5 Wei Zhao1,2 1Medical School, Southeast University, Nanjing, People’s Republic of China; 2Department of Liver Disease, The Second Hospital of Nanjing, Medical School, Southeast University, Nanjing, People’s Republic of China; 3Department of Hematology and Oncology, Geriatric Hospital of Nanjing Medical University, Jiangsu Province Geriatric Hospital, Nanjing, People’s Republic of China; 4Department of Pathology, Pukou District Central Hospital, Pukou Branch of Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 5Department of Pathology, Jiangsu Cancer Hospital, Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei ZhaoMedical School, Southeast University, 87 Dingjiaqiao Street, 210000 Nanjing, Jiangsu, People’s Republic of ChinaTel +86 25 8362-6000Fax +86 25 8362-6060Email weizhaoseu@163.comPurpose: Although MAGEC2 was first cloned from a human hepatocellular carcinoma (HCC) cDNA library by serum screening, the detailed attributes of MAGEC2 in HCC have rarely been elucidated.Patients and methods: In this study, The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases were consulted to analyse the expression of MAGEC2 mRNA in liver cancer. Immunohistochemistry (IHC) analysis was performed to detect MAGEC2 expression in HCC, and the relationship between MAGEC2 expression and the clinicopathological characteristics of HCC patients was evaluated. Then, we employed the short hairpin (sh)RNA-mediated knockdown of MAGEC2 in HCC cell lines to explore the function of MAGEC2 in HCC development. Finally, the expression of epithelial-mesenchymal transition (EMT) markers in HCC xenografts and clinical samples was investigated.Results: The results showed a remarkably higher level of MAGEC2 expression in HCC tissues than in noncancerous tissues, and MAGEC2 expression could be used as an independent prognostic factor for overall survival in HCC. Moreover, sh-MAGEC2 inhibited a series of HCC malignant behaviours both in vitro and in vivo. Finally, decreased MAGEC2 expression and low levels of EMT markers were detected in sh-MAGEC2 xenografts, while increased MAGEC2 expression and high levels of EMT markers were observed in invasive and metastatic HCC samples.Conclusion: Taken together, our data imply that MAGEC2 is a novel prognostic marker for HCC and that MAGEC2 significantly promotes HCC tumourigenesis by inducing EMT. Targeting MAGEC2 may provide a promising therapeutic strategy for HCC treatment.Keywords: MAGEC2, hepatocellular carcinoma, prognosis, tumourigenesis, EMT

Xiaohui Zhao,1,* Tian Xie,1,* Wenhui Zhao,2,3,* Wanhua Cai,1 Xiaobo Su1 1GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou 511436, China; 2State Key Laboratory of Oncology in Southern China, Sun Yat-sen University, Cancer Center, Guangzhou 510060, China; 3Juancheng People’s Hospital, Juancheng 274600, China *These authors contributed equally to this work Background: Recently, the biggest challenge in the treatment of breast cancer is the metastasis of breast cancer cells. Multiple myeloma SET protein (MMSET), a histone lysine methyltransferase, overexpressed in various human cancers, was reported to be associated with carcinogenesis of human cancers. Methods: Expression of MMSET in breast cancer cell lines and tissues was quantified by real-time PCR and Western blotting. Immunohistochemistry was employed to analyze MMSET expression in 163 clinicopathologically characterized breast cancer cases. Cell functional assays such as MTT assay, colony formation, BrdU assay, flow cytometry, wound healing, Transwell assay, and 3D culture were used to investigate the effect of MMSET in the development and metastasis of human breast cancer. Effects of MMSET on Wnt/β-catenin signaling pathway were further studied by using Western blotting analysis. Results: Our results showed that MMSET expression was markedly overexpressed in breast cancer cells and clinical specimens and was significantly correlated with patients’ clinicopathologic characteristics and prognosis. Moreover, silencing endogenous MMSET significantly inhibited the proliferation, migration, and metastasis of breast cancer cells through inhibiting the Wnt/β-catenin pathway. Conclusion: This study found that the downregulated expression of MMSET impaired proliferation and metastasis of human breast cancer through inhibiting Wnt/β-catenin signaling pathway. Notably, our results indicated that MMSET could be a useful biomarker for the prognosis of breast cancer. Keywords: multiple myeloma SET protein, carcinogenesis, patient’s clinicopathologic characteristics, prognosis, biomarker

Wei Zhao,1,2 Wancheng Li,3 Wenjing Dai,3 Na Huang,3 Jing Qiu3 1Department of Clinical Biochemistry, School of Laboratory Medicine, Chengdu Medical College, Chengdu, People’s Republic of China; 2Department of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing, People’s Republic of China; 3Department of Respiratory Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, People’s Republic of China Purpose: Non-small-cell lung cancer (NSCLC) is the one of the most common malignancies worldwide, and occurs at a higher frequency in male individuals. Little is known about the role of the long intergenic noncoding RNA for kinase activation (LINK-A) in NSCLC, so in the present study we assessed its potential role on cell proliferation in NSCLC. Methods: Expression levels of LINK-A in NSCLC tissues and cell lines were detected by quantitative reverse-transcription polymerase chain reaction. LINK-A was knocked down and overexpressed separately in A549 cells and NCI-H1299 cells. The effect of LINK-A expression on cell proliferation was determined by MTT assay. The correlation between LINK-A and hexokinase II (HKII) expression was investigated by Western blot and HKII Activity Assay. Glucose consumption and lactate production assay were used to investigate the aerobic glycolysis in NSCLC cells. The effect of LINK-A in vivo was determined by xenograft assay. Results: LINK-A expression levels were increased in NSCLC tissues compared with normal tissues. Moreover, LINK-A expression was positively correlated with NSCLC clinicopathological characteristics and survival rate, while knockdown of LINK-A reduced NSCLC cell proliferation. LINK-A expression was also positively correlated with HKII, and NSCLC cells with low LINK-A expression were found to have significantly reduced HKII protein expression, accompanied by a reduction in enzyme activity levels. Both in vitro and in vivo experiments showed that LINK-A expression affected glucose consumption and lactate production through regulation of HKII expression. Conclusion: These data suggest that the functions of LINK-A in NSCLC might play a key role in tumor progression and that LINK-A could be a promising predictive biomarker and potential therapeutic target for NSCLC. Keywords: non-small-cell lung cancer, LINK-A, proliferation, hexokinase II, aerobic glycolysis, prognosis

Xiaoping Ouyang,1,2 Yumin Huang,2 Xing Jin,3 Wei Zhao,4,5 Tao Hu,2 Feng Wu,2 Jianan Huang1 1Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 2Department of Respiratory Medicine, The Affiliated Hospital of Yangzhou University, Yangzhou, People’s Republic of China; 3Department of Clinical Laboratory, The Affiliated Hospital of Yangzhou University, Yangzhou, People’s Republic of China; 4Department of Clinical Biochemistry, School of Laboratory Medicine, Chengdu Medical College, Chengdu, People’s Republic of China; 5Department of Pulmonary Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing, People’s Republic of China Background: Osteopontin (OPN), a member of the small integrin binding ligand N-linked glycoprotein family, has been analyzed in numerous types of human malignancy. Purpose: The present study detected the expression levels of OPN and evaluated its role in tumor progression in patients with non-small cell lung cancer (NSCLC). Patients and methods: OPN expression levels were detected using immunohistochemistry in 101 NSCLC tumors. The mRNA and protein levels have significant difference between advanced NSCLC and stage I/II NSCLC. The drug resistance, invasive ability and lactate production of NSCLC cancer cell lines (A549 and SK-MES-1) were detected in cancer cells with the disturbance of OPN. Results: Immunostaining indicated that OPN was primarily expressed in the cytoplasm of NSCLC cells. Moreover, OPN correlates with NSCLC clinical traits. The results demonstrated that OPN expression levels significantly correlated with cancer differentiation, distant metastasis and the efficacy of platinum-based treatment. Notably, the results identified OPN expression levels as a potential factor for predicting the response of cells to first-line platinum-based chemotherapy using multivariate analysis, as well as predicting cancer differentiation and distant metastasis. Additionally, the abrogation of OPN levels reduced lactate production in NSCLC cells and occurred along side with the downregulation of lactate dehydrogenase A (LDHA). Conclusion: The results of the current study suggest that OPN may be able to predict poor prognosis and cisplatin resistance in patients. Keywords: osteopontin, non-small-cell lung cancer, clinical outcome, drug resistance, invasion, lactate production

Wei Jiang,1,* Qitao Yu,1,* Ruiling Ning,1 Wenhua Zhao,1 Changyuan Wei2 1Department of Medical Oncology, Tumor Hospital Affiliated to Guangxi Medical University, Nanning, People’s Republic of China; 2Department of Breast Surgery, Tumor Hospital Affiliated to Guangxi Medical University, Nanning, People’s Republic of China *These authors contributed equally to this work Background: Results from several prospective clinical trials comparing anti-epidermal growth factor receptor (EGFR) therapy and anti-vascular endothelial growth factor (VEGF) therapy plus chemotherapy for wild-type RAS metastatic colorectal cancer (mCRC) have been inconsistent. This meta-analysis aims to investigate the optimal choice for these target agents. Methods: We searched for clinical trials in both electronic databases from inception until January 2018 and recent conference abstracts to identify prospective clinical studies comparing the efficacy of a VEGF inhibitor (bevacizumab) versus EGFR inhibitors (cetuximab or panitumumab) on wild-type RAS (including its subset KRAS) mCRC. All analyses were conducted using RevMan 5.3 software. Results: A total of 5 studies were included. EGFR inhibitors were associated with a significant benefit in terms of overall survival (OS) compared with VEGF inhibitors in wild-type KRAS or wild-type RAS populations, with hazard ratios (HRs) equal to 0.86 (95% CI: 0.78, 0.95; p=0.003) and 0.83 (95% CI: 0.72, 0.95; p=0.007), respectively. This survival benefit was limited to the first-line setting. No difference was found for progression-free survival (PFS), whereas the objective response rate (ORR) was significantly increased in the wild-type RAS population (OR: 0.64; 95% CI: 0.50, 0.82; p=0.0004). No difference in OS was noted between EGFR inhibitors versus a VEGF inhibitor plus the FOLFIRI regimen, whereas superior survival was noted for EGFR inhibitors plus the mFOLFOX6 regimen versus a VEGF inhibitor (HR: 0.75; 95% CI: 0.57, 0.98; p=0.04). PFS was significantly prolonged (HR: 1.48; 95% CI: 1.14, 1.92; p=0.003), whereas a trend favoring OS (HR: 1.23; 95% CI: 0.93, 1.63; p=0.14) was noted for a VEGF inhibitor in patients with right-sided tumors, with no difference in the ORR (OR: 0.85; 95% CI: 0.52, 1.38; p=0.51). However, left-sided tumors exhibited superior OS (HR: 0.71; 95% CI: 0.59, 0.85; p=0.0002), PFS (HR: 0.84; 95% CI: 0.72, 0.98; p=0.03), and ORR (OR: 0.66; 95% CI: 0.48, 0.92; p=0.01) for EGFR inhibitors. Conclusion: This meta-analysis suggests the superiority of anti-EGFR therapy compared with anti-VEGF therapy for mCRC with wild-type RAS. Primary tumor location should be taken into account in target drug selection. Further research is still needed to confirm which inhibitor may be a better choice when combined with different chemotherapy regimens. Keywords: bevacizumab, cetuximab, panitumumab, colorectal cancer, meta-analysis

Xin Yang, Rui Chen, Chen Wu, Weiqing Zhao, Mei Ji Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China Abstract: Rapid metastasis contributes significantly to the high mortality rates in lung adenocarcinoma. The present study reports a rare case of primary lung adenocarcinoma with concomitant gastric, duodenal, bone, and mediastinal lymph node metastases. A large gene panel based on the next-generation sequencing was used to detect gene mutations in different metastatic sites and blood. The results showed that the gene mutation spectrums among different metastatic foci were roughly similar. The mutation abundance was highest in mediastinal lymph nodes. Unique mutation sites were detected only in mediastinal lymph nodes, bone, and gastric metastatic foci. Despite partial heterogeneity, there are currently no applicable targeted drugs to adopt. In addition, tumor mutation burden (TMB) showed that blood, gastric, bone, and mediastinal lymph node metastases were all TMB-High, while the duodenal metastasis was TMB-Low. This study is the first to report a rare case of newly diagnosed lung adenocarcinoma with concomitant gastrointestinal metastases and to perform mutation analyses on all metastatic foci. Large sample sizes with similar cases are required to gain deeper insights. Keywords: lung adenocarcinoma, gastric metastasis, duodenal metastasis, TMB

Junliang Yao, Jingtian Liu, Wensheng Zhao Department of General Surgery, Jinshan Hospital, Affiliated to Fudan University, Shanghai, People’s Republic of China Introduction: The purpose of present study was to investigate the effect of limonin on tumor glycolysis and the underlying mechanisms in hepatocellular carcinoma (HCC). Methods: Cell proliferation and colony formation assays were performed to evaluate the potency of limonin against HCC cells in vitro. The glucose consumption and lactate production after limonin treatment was determined. The effect of limonin on hexokinase-2 ( HK-2) activity was assessed and the mitochondrial location of HK-2 was studied by immunoprecipitation. Cell apoptosis and protein expression were detected by flow cytometry and western blotting respectively. Protein overexpression by plasmid transfection was adopted to investigate the molecular mechanisms. Results: HCC proliferation and colony formation were inhibited by limonin in vitro. With the suppression of HK-2 activity, the glycolytic level in HCC cells was substantially reduced, which was evidenced by the decrease of glucose consumption and lactate production. The phosphorylation of HK-2 was substantially inhibited by limonin, which resulted in the disassociation of HK-2 from mitochondria. Due to the reduction of HK-2 in mitochondria, increasing Bax were shifted to the mitochondria and gave rise to the release of cytochrome C, which induced HCC cells to subject to mitochondria-mediated apoptosis. Mechanism investigations revealed that the decrease of HK-2 phosphorylation was mainly due to the inhibition of Akt activity. In Akt exogenously overexpressed HCC cells, limonin-mediated cell proliferation inhibition, glycolysis suppression and apoptosis induction were significantly impaired. Conclusion: Limonin inhibited the tumor glycolysis in hepatocellular carcinoma by suppressing HK-2 activity, and the suppression of HK-2 was closely related to the decrease of Akt activity. Keywords: apoptosis, limonin, tumor glycolysis, hexokinase-2

Tingting Zhang,1 Fubin Feng,2 Wenge Zhao,3 Jinhui Tian,4 Yan Yao,3 Chao Zhou,2 Shengjie Dong,5 Congcong Wang,6 Chuanxin Zang,1 Qingliang Lv,7 Changgang Sun2,8 1College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, WeiFang, China; 2Department of Oncology, Weifang Traditional Chinese Hospital, WeiFang, China; 3Department of Oncology, Clinical Medical Colleges, Weifang Medical University, WeiFang, China; 4Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China; 5Department of the Joint and Bone Surgery, Yantaishan Hospital, Yantai, China; 6Department of Oncology, Zibo Maternal and Child Health Hospital, Zibo, China; 7Department of Radiology, Weifang people’s Hospital, WeiFang, China; 8Department of Oncology, Affiliated Hospital of Weifang Medical University, WeiFang, China Background: Endocrine therapy is the cornerstone treatment for patients with hormone receptor-positive advanced breast cancer. We aimed to assess the effectiveness of various first-line endocrine monotherapies or combinations to determine the optimal sequence in a network meta-analysis. Materials and methods: We searched PubMed, EMBASE, and the Cochrane Library for randomized controlled trials (RCTs) from inception up to November 21, 2017. We included only RCTs that assessed the effectiveness of the following treatments as a monotherapy or in combination as the first-line treatment: tamoxifen, anastrozole, letrozole, exemestane, fulvestrant, palbociclib, and ribociclib. The results were presented with pooled odds ratio or hazard ratio (HR), and 95% credible interval (CrI). The primary outcomes were objective response rate (ORR) and progression-free survival/time to progression. Results: A total of 16 eligible articles (14 RCTs) involving 6,602 patients treated with 10 different first-line endocrine therapies were assessed in our network meta-analysis. Palbociclib plus letrozole was superior to anastrozole, letrozole, exemestane, fulvestrant 500 mg, and anastrozole plus fulvestrant (loading dose) (HR=0.44, 95% CrI: 0.33–0.58; HR=0.56, 95% CrI: 0.45–0.68; HR=0.45, 95% CrI: 0.32–0.61; HR=0.58, 95% CrI: 0.42–0.81; HR=0.50, 95% CrI: 0.37–0.68; respectively). However, there is no significant advantage compared with ribociclib plus letrozole (HR=1.00, 95% CrI: 0.72–1.39). In terms of ORR, ribociclib plus letrozole is more effective than palbociclib plus letrozole (odds ratio=1.30, 95% CrI: 0.83–2.02). Conclusion: Palbociclib plus letrozole and ribociclib plus letrozole might be the optimal first-line endocrine therapeutic choices for hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer due to a longer progression-free survival/time to progression and a more efficacious ORR. Keywords: first-line endocrine therapy, progression-free survival, objective response rate, advanced breast cancer, network meta-analysis, randomized controlled trial

Ming Sun,1 Zhaofu Chen,1 Shutao Tan,1 Caigang Liu,2 Wenyan Zhao3 1Department of Urology, 2Department of Breast Surgery, 3Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China Background: FSIP1 plays a vital role in tumorigenesis and cancer progression. In bladder cancer, FSIP1 overexpression was associated with poor prognosis of bladder urothelial carcinoma. In this study, we investigated whether FSIP1 is essential in the progression of bladder cancer and the mechanism by which it mediates this effect.Methods: FSIP1 expression was knocked down in bladder cancer cells using lentiviral-mediated short hairpin RNA (shRNA). FSIP1 expression was detected using Western blotting, immunohistochemistry (IHC), and quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). The effects of FSIP1 knockdown on tumor cells were assessed using colony formation, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and flow cytometry (FCM) apoptosis assays in vitro and BALB/c nude mouse xenograft model in vivo.Results: The findings suggested that FSIP1 protein was highly expressed in bladder cancer cell lines. Knockdown of FSIP1 resulted in reduced tumor cell viability, cell cycle arrest at G0/G1 phase and apoptosis of bladder cancer cell lines (P

Wenge Zhao,1,* Chuanxin Zang,2,* Tingting Zhang,2 Jia Li,1 Ruijuan Liu,3 Fubin Feng,3 Qingliang Lv,4 Liang Zheng,5 Jinhui Tian,6 Changgang Sun3 1Department of Oncology, College of Clinical Medicine, Weifang Medical University, Weifang, People’s Republic of China; 2College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of China; 3Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, People’s Republic of China; 4Department of Interventional Radiology, Weifang People’s Hospital, Weifang, People’s Republic of China; 5Department of Cardiovascular Medicine, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China; 6Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, People’s Republic of China *These authors contributed equally to this work Background: The clinicopathological and prognostic values of the cancer stem cell marker aldehyde dehydrogenase 1 (ALDH1) in ovarian cancer (OC) remain unknown. The aim of our meta-analysis was to evaluate ALDH1’s association with clinicopathological characteristics and its prognostic significance in patients with OC. Materials and methods: PubMed, Embase, and China Biology Medicine were systematically searched for eligible studies (up to October 2017). Pooled odds ratios (ORs) or hazard ratios (HRs) with 95% CIs were used to evaluate the association of ALDH1 expression with clinicopathological features and survival outcomes. Results: A total of 17 papers (18 studies) that included 2,531 patients with OC were analyzed. The results showed a significant association between increasing ALDH1 expression and International Federation of Gynecology and Obstetrics stage (OR 2.02, 95% CI 1.16–3.52), lymph node metastasis (OR 1.91, 95% CI 1.01–3.61), and distant metastasis (OR 5.43, 95% CI 1.44–20.42) in OC. However, no significant correlation was found between increasing ALDH1 expression and age (OR 0.90, 95% CI 0.25–3.28), tumor size (OR 1.13, 95% CI 0.75–1.71), tumor location (OR 0.69, 95% CI 0.22–2.13), ascite status (OR 0.74, 95% CI 0.49–1.11), resistance status (OR 0.70, 95% CI 0.14–3.51), or clinicopathological type (OR 1.14, 95% CI 0.69–1.86). Moreover, a high ALDH1 expression was significantly associated with overall survival (HR 1.56, 95% CI 1.21–2.02) but not with disease-free survival (HR 1.38, 95% CI 0.99–1.93). Conclusion: The meta-analysis indicates that increasing ALDH1 predicts poor prognosis and clinicopathological characteristics in OC. Future studies are needed to explore tailored treatments that directly target ALDH1 for the improvement of survival in OC. Keywords: ovarian cancer, ALDH1, prognosis, clinicopathological characteristics, meta-analysis

Ming Sun,1 Wenyan Zhao,2 Yuecan Zeng,3 Di Zhang,4 Zhaofu Chen,1 Caigang Liu,5 Bin Wu1 1Department of Urology, 2Department of General Surgery, 3Department of Medical Oncology, Shengjing Hospital of China Medical University, 4Department of Pathology, the First Affiliated Hospital and College of Basic Medical Sciences of China Medical University, 5Department of Breast Cancer Surgery Center, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of China Abstract: The study aimed to investigate the clinical significance of fibrous sheath interacting protein 1 (FSIP1) in bladder cancer, and its potential relevance to the survival of patients with bladder cancer. A total of 225 surgical excised-bladder cancer tissues were collected from the patients with the follow-up data >5 years. The FSIP1 expressions were assayed using immunohistochemistry. The messenger RNA (mRNA) and/or protein levels of FSIP1 in fresh bladder tumor tissues as well as bladder cancer cell lines were measured by quantitative real-time polymerase chain reaction (PCR) and Western blotting analysis. The correlation of FSIP1 expression with clinicopathological parameters was also evaluated. Western blotting analysis revealed that FSIP1 protein was detected in 94.1% (16/17) of bladder tumor specimens and in all three bladder cancer cell lines (5637, BIU-87, and T24 in particular), with significantly higher expression than those of their controls. Quantitative real-time PCR demonstrated an increased FSIP1 mRNA expression level in bladder cancer tissues than in normal adjacent tissues (P=0.012). FSIP1 overexpression showed good correlation with tumor stage and lymph node metastasis (P=0.027 and 0.000, respectively). Positive FSIP1 expression was independently associated with an unfavorable overall and disease-free survival by multivariate Cox regression (P=0.037 and 0.019, respectively). FSIP1 overexpression is associated with unfavorable prognosis in patients with bladder cancer. Thus, FSIP1 represents a potential therapeutic or predictive target for bladder cancer. Keywords: bladder cancer, fibrous sheath interacting protein 1, prognosis, survival, metastasis

Yong Wang,1,* Jie Sun,2,* Xilin Wei,3 Lan Luan,2 Xiandong Zeng,4 Cuifang Wang,2 Wei Zhao1 1The 4th Department of Orthopedic Surgery, Central Hospital affiliated to Shenyang Medical College, Shenyang, 2Department of Pathology, Central Hospital affiliated to Shenyang Medical College, Shenyang, 3The 3rd Department of General Surgery, Central Hospital affiliated to Shenyang Medical College, Shenyang, 4Department of Surgical Oncology, Central Hospital affiliated to Shenyang Medical College, Shenyang, People’s Republic of China *These authors contributed equally to this work Background: More and more evidence indicates that microRNAs are present and involved in many tumor-related diseases. The function of microRNA-622 (miR-622) in colorectal cancer (CRC) remains controversial. Dual specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) has been reported as a tumor suppressor gene in different cancers. The detailed regulation mechanism of DYRK2 in CRC remains unclear. Methods: miR-622 and DYRK2 expression levels were detected at tissue and cellular level respectively by using real time polymerase chain reaction (PCR), Western blot, and immunohistochemical staining. Pearson’s correlation analysis was used to evaluate the correlation between miR-622 and DYRK2. Transwell assay was applied to measure the effect of miR-622 on migration and invasion of SW1116 and SW480. We used dual luciferase reporter assay to confirm the targeted binding effect of miR-622 and DYRK2 3'-untranslated region (3'UTR). An antisense experiment was executed to further confirm the role miR-622 had played with regard to migration and invasion by targeting regulation of DYRK2 pathway in CRC cells. Results: In our research, we found that the expression of miR-622 was elevated in CRC tissues and cell lines compared to that of nonCRC tissues and the normal human colon epithelial cell line NCM460. Correspondingly, the expression of DYRK2 in CRC tissues and cell lines showed a contrary tendency. The different expression level of DYRK2 was closely correlated with clinicopathological characteristics of CRC patients. We demonstrated that down-regulation of miR-622 could inhibit the ability of migration and invasion of CRC cell lines SW1116 and SW480. Also, we confirmed that DYRK2 was negatively regulated by miR-622 via a specific targeted binding site within the 3'UTR. We finally verified that the migration and invasion ability of CRC cells in the conducted DYRK2 3'UTR defect plasmid transfection group were lower compared to miR-622 and cotransfection group. Conclusion: The findings of this study indicate that a decrease of miR-622 expression could suppress migration and invasion by targeting regulation of DYRK2 and miR-622/DYRK2 could be a potential molecular treating target of CRC. Keywords: miR-622, DYRK2, migration, invasion, colorectal cancer

Xuemei Sui,1,* Hong Zhou,2,* Lei Zhu,3 Deqiang Wang,4 Sumei Fan,5 Wei Zhao6 1Clinical Laboratory, The First Affiliated Huai’an Hospital of Nanjing Medical University, 2Huai’an No 4 People’s Hospital, Huai’an, 3Department of Digestive System, Jiangsu Province Hospital of TCM, Nanjing, 4Cancer Therapy Center, Affiliated Hospital of Jiangsu University, Zhenjiang, 5Geriatric Department, The Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, 6Clinical Laboratory, Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China *These authors contributed equally to this work Abstract: Increasing evidence suggests that CUL4A, a ubiquitin ligase, is involved in the promotion of cancer malignancy and correlated with worse clinical prognosis in several kinds of human cancers. Although its effect and mechanism on the progression of colorectal cancer (CRC) remain unknown. Our clinical data show that CUL4A protein is overexpressed, positively associated with lymph nodes status, differentiation degree, tumor size, and poor prognosis in 80 CRC patients. CUL4A overexpression promotes cell proliferation and colony formation of CRC cells. Knockdown of CUL4A inhibits cell proliferation and migration. CUL4A can significantly promote the in vitro migration of CRC cells via induction of the epithelial–mesenchymal transition process. And the modulation of CUL4A expression altered the level of H3K4 trimethylation at the E-cadherin, N-cadherin, and vimentin gene promoters, which in turn transcriptionally regulated their expression. Moreover, knockdown of CUL4A also decreased the tumor volume and tumor weight in vivo. Together, our results reveal that CUL4A plays as an oncogene in CRC and may become a potential therapeutic target in the treatment of colorectal cancer. Keywords: colorectal cancer, CUL4A, EMT, migration, H3K4 trimethylation

Wuli Zhao, Caixia Zhang, Chongwen Bi, Cheng Ye, Danqing Song, Xiujun Liu, Rongguang Shao Key Laboratory of Antibiotic Bioengineering, Ministry of Health, Laboratory of Oncology, Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People’s Republic of China Abstract: Sophoridine is a quinolizidine natural product of Sophora alopecuroides and has been applied for treatment of malignant trophoblastic tumors. Although characterized by low toxicity, the limited-spectrum antitumor activity hinders its further applications. 05D, a derivative of sophoridine, exhibits a better anticancer activity on diverse cancer cells, including solid tumors, and hematologic malignancy. It could inhibit topoisomerase 1 (top1) activity by stabilizing DNA–top1 complex and induce mitochondria-mediated apoptosis by promoting DNA single- and double-strand breakage mediated by top1. Also, 05D induced HCT116 cells arrest at G1 phase by inactivating CDK2/CDK4–Rb–E2F and cyclinD1–CDK4–p21 checkpoint signal pathways. 05D suppressed the ataxia telangiectasia mutated (ATM) and ATM and Rad3-related (ATR) activation and decreased 53BP level, which contributed to DNA damage repair, suggesting that the novel compound 05D might be helpful to improve the antitumor activity of DNA damaging agent by repressing ATM and ATR activation and 53BP level. In addition, the priorities in molecular traits and druggability, such as a simple structure and formulation for oral administration, further prove 05D to be a promising targeting topoisomerase agent. Keywords: topoisomerase inhibitor, topoisomerase 1, DNA breakage, sophoridinol, anticancer, apoptosis, cell cycle

Wei Zhao, Jing Gao, Jing Wu, Qiu-hong Liu, Zhi-gang Wang, Hui-ling Li, Li-hua Xing The Third Department of Respiratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China Background: Lung cancer poses a severe threat to human life. Biomarkers of cancers are helpful in the diagnosis and treatment of patients with cancers. Biomarkers of lung cancers are rare, and thus deserve further research.Objective: The objective of the present study was to explore the expression of Fascin-1 in human lung cancer and paracarcinoma tissue, its correlation with clinicopathological characteristics in patients with lung cancer, and study the possible relationship between Fascin-1 expression and clinical–biological behavior of lung cancer.Method: This study used the MaxVision two-step immunohistochemical detection method to detect Fascin-1 expression in 84 of lung cancer and paracarcinoma tissues. This study set the expression of Fascin-1 in vascular endothelial cells as the positive control, and used phosphate buffered saline (replacing the primary antibodies) as negative control.Result: Of all the 84 lung cancer tissues and paracarcinoma tissues, positive expression of the Fascin-1 protein were detected in 78 cases (92.9%) and 27 cases (32.1%), respectively, and the difference was statistically significant (P0.05). The survival times of the patients with different Fascin-1 protein-positive expressions in lung cancer tissues were statistically significant (P0.05).Conclusion: In lung cancer, Fascin-1 expression was closely related to tumor invasion and metastasis, and the difference in expression of Fascin-1 had a significant effect on the survival time of the lung cancer patients. Therefore, Fascin-1 might be expected to serve as a possible potential biomarker of lung cancer. Keywords: pulmonary carcinoma, Fascin-1 protein, immunohistochemistry, survival time