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Camrelizumab, an anti-PD-1 antibody, has shown moderate efficacy in oesophageal squamous cell carcinoma. Apatinib, a selective inhibitor of VEGFR2, has a synergistic effect with immunotherapy. We aimed to assess the combination of camrelizumab and apatinib as second-line treatment for advanced oesophageal squamous cell carcinoma.This single-arm, open-label, phase 2 study was conducted at eight centres in China. Eligible patients were aged 18-75 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, who had unresectable locally advanced, locally recurrent, or metastatic oesophageal squamous cell carcinoma, and had progressed after or were intolerant to first-line chemotherapy. Patients received intravenous camrelizumab 200 mg once every 2 weeks plus oral apatinib 250 mg once daily for a 28-day cycle until disease progression, unacceptable adverse events, or withdrawal of consent. The primary endpoint was investigator-assessed confirmed objective response rate. Efficacy was analysed in patients who had received at least one dose of study drug, and safety was analysed in patients who received the study drug and had at least one post-baseline safety assessment. The study of this cohort is complete and this trial is registered with ClinicalTrials.gov, number NCT03736863.Between Dec 5, 2019, and Feb 10, 2021, 52 patients were enrolled and included in analyses. At data cutoff (June 20, 2021), median follow-up was 7·5 months (IQR 4·0-11·2). 18 (34·6%, [95% CI 22·0-49·1]) of 52 patients had a confirmed objective response. 23 (44%) of 52 patients had grade 3 or worse treatment-related adverse events. The most common grade 3 or worse treatment-related adverse events were increased aspartate aminotransferase (10 [19%]), increased gamma-glutamyltransferase (10 [19%]), and increased alanine aminotransferase (five [10%]). No treatment-related deaths occurred.Camrelizumab combined with apatinib showed promising activity and manageable toxicity, and might be a potential second-line treatment option for patients with advanced oesophageal squamous cell carcinoma. Another cohort of this study, enrolling patients previously treated with first-line immunotherapy, is ongoing.Jiangsu Hengrui Pharmaceuticals.

Long non‐coding RNAs (lncRNAs) widely participate in ESCC development and progression; however, the prognostic factors and therapeutic strategies implicated in ESCC development and progression remain to be under investigation. The purpose of the current study was to explore whether WDFY3‐AS2 may be a potential prognostic factor and investigate its biological functions in ESCC. Here, WDFY3‐AS2 was frequently down‐regulated in ESCC tissues and cells, and its expression was correlated with TNM stage, lymph node metastasis and poor prognosis of ESCC patients. Moreover, WDFY3‐AS2 down‐regulation significantly promoted cell proliferation and invasion, whereas WDFY3‐AS2 up‐regulation markedly suppressed cell proliferation and invasion in ESCC EC9706 and TE1 cells, coupled with EMT phenotype alterations. WDFY3‐AS2 functioned as a competing endogenous RNA (ceRNA) for sponging miR‐2355‐5p, further resulted in the up‐regulation of its target gene SOCS2, followed by suppression of JAK2/Stat5 signalling pathway, to suppress ESCC cell proliferation and invasion in EC9706 and TE1 cells. These findings suggest that WDFY3‐AS2 may participate in ESCC development and progression, and may be a novel prognostic factor for ESCC patients, and thus targeting WDFY3‐AS2/miR‐2355‐5p/SOCS2 signalling axis may be a novel therapeutic strategy for ESCC patients.

ObjectivesVarious blood inflammatory biomarkers were associated with treatment response and prognosis of non-small cell lung cancer (NSCLC) in previous studies. In this study, we retrospectively evaluated the prognostic role of pretreatment blood inflammatory biomarkers and epidermal growth factor receptor (EGFR) mutation status in stage IIIA/N2 NSCLC patients with trimodality therapy.MethodsCompletely resected stage IIIA/N2 NSCLC patients with adjuvant chemotherapy and postoperative radiotherapy (PORT) were assessed in this study. Cutoff values of blood inflammatory factors were calculated by the R package SurvivalROC of R software. SPSS Statistics software was used for survival analyses. Kaplan-Meier survival curve and log-rank test were used to compare the survival difference between every two groups. Univariate and multivariate analyses of predictive factors were performed by Cox proportional hazards regression model.ResultsThe univariate analysis showed that T stage (p=0.007), EGFR mutation status (p=0.043), lymphocyte-to-monocyte ratio (LMR) (p=0.067), and systemic immune-inflammation index (SII) (p=0.043) were significant prognostic factors of disease-free survival (DFS). In the multivariate analysis, T2 (HR=0. 885, 95% CI: 0.059-0.583, p=0.004), EGFR mutation-positive (HR=0.108, 95% CI: 0.023-0.498, p=0.004) and elevated pretreatment SII (HR=0.181, 95%CI: 0.046-0.709, p=0.014) were independently related to shorter DFS. High pretreatment neutrophil counts (HR=0.113, p=0.019) and high systemic inflammation response index (SIRI) (HR=0.123, p=0.025) were correlated with worse overall survival (OS) by the univariate analysis. In the multivariate analysis, only high pretreatment SIRI was an independent predictor for poorer OS (HR=0.025, 95% CI: 0.001-0.467, p=0.014).ConclusionsIn conclusion, we identified that high pretreatment SII and SIRI were unfavorable prognostic factors in stage IIIA/N2 NSCLC patients treated with surgery, adjuvant chemotherapy and PORT. Patients with high pretreatment SII, high pretreatment SIRI, T2, and EGFR mutation-positive may need more forceful adjuvant treatment. Further prospective studies with large-scale are needed to validate our results and identify the proper cut-off values and optimum adjuvant treatment for distinct patient population.

LINC00184 has been suggested to be associated with cancer prognosis and has been implicated in cancer glycolysis; however, its role in oesophageal squamous cell carcinoma (ESCC) remains poorly understood. Herein, to understand the expression and the biological roles of LINC00184 in ESCC, in situ hybridization (ISH) and quantitative PCR (qPCR) were performed to detect the expression of LINC00184 in tissue blocks and in fresh tissues, respectively. Furthermore, with an in vitro cell culture system, LINC00184 was stably knocked down in ESCC cell lines KYSE-150 and Eca109, followed by determining alterations in their proliferation and motility relative to control. To gain insight into the regulation of LINC00184, STAT3 was bioinformatically identified as a transcription factor of LINC00184, which was further corroborated by chromatin-immunoprecipitation (CHIP) assay. The dephosphorylation of STAT3 with NSC74859 was shown to be unable to suppress the expression of LINC00184 in vivo in a xenograft mouse model. Moreover, STAT3, once phosphorylated at serine 727, tended to translocate into the mitochondria to promote LINC00184 expression in ESCC cells. Together, these data strongly support the oncogenic role of LINC00184 in ESCC.

BackgroundWe aimed to explore the role of local ablative treatment (LAT) in metastatic esophageal squamous cell cancer (ESCC) patients who received chemotherapy and identify patients who will most likely benefit.MethodsWe analyzed data of metastatic ESCC patients from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2016. The chi-square test was used to evaluate the unadjusted clinicopathological categorical variables between the two groups. Univariate and multivariate Cox regression analyses were conducted to identify independent prognostic factors of overall survival. Propensity score matching (PSM) was used to adjust the differences between the two groups.ResultsOverall, 720 metastatic ESCC patients treated with chemotherapy were analyzed in this study; 63.2% of patients (n = 455) received LAT, including radiotherapy (n = 444), primary site surgery (n = 12), or lymph node dissection (n = 27). Gender (HR = 1.220, 95% CI: 1.024–1.453, p = 0.026), bone metastases (HR = 1.559, 95% CI: 1.292–1.882, p < 0.001), and liver metastases (HR = 1.457, 95% CI: 1.237–1.716, p < 0.001) were independent prognostic factors in the entire population. However, LAT was not an independent prognostic factor. Further subgroup analyses showed that LAT improved OS from 8.0 months to 10.0 months in patients with metastases other than bone/liver (HR = 0.759, 95% CI: 0.600–0.961, p = 0.022). LAT was not a prognostic factor in patients with bone/liver metastases (HR = 0.995, 95% CI: 0.799–1.239, p = 0.961). After PSM, the median OS was 8.0 months (95% CI: 7.2–8.8 months) and patients who received LAT had a better OS than patients without LAT (HR = 0.796, 95% CI: 0.653–0.968, p = 0.023). Patients with metastases other than bone/liver could benefit from LAT compared with those with bone/liver metastases.ConclusionsOur study indicated that metastatic ESCC patients with metastases other than bone/liver could derive additional benefit from LAT with systemic chemotherapy.

Background Emerging evidence demonstrates that lncRNAs play pivotal roles in tumor energy metabolism; however, the detailed mechanisms of lncRNAs in the regulation of tumor glycolysis remain largely unknown. Methods The expression of SLC2A1-AS1 was investigated by TCGA, GEO dataset and qRT-PCR. The binding of GLI3 to SLC2A1-AS1 promoter was detected by Luciferase Reporter Assay System and Ago2-RIP assay. FISH was performed to determine the localization of SLC2A1-AS1 in ESCC cells. Double Luciferase Report assay was used to investigate the interaction of miR-378a-3p with SLC2A1-AS1 and Glut1. Gain-of-function and Loss-of-function assay were performed to dissect the function of SLC2A1-AS1/miR-378a-3p/Glut1 axis in ESCC progression in vitro and in vivo. Results We identified a novel lncRNA SLC2A1-AS1 in ESCC. SLC2A1-AS1 was frequently overexpressed in ESCC tissues and cells, and its overexpression was associated with TNM stage, lymph node metastasis and poor prognosis of ESCC patients. Importantly, GLI3 and SLC2A1-AS1 formed a regulatory feedback loop in ESCC cells. SLC2A1-AS1 promoted cell growth in vitro and in vivo, migration and invasion, and suppressed apoptosis, leading to EMT progression and increased glycolysis in ESCC cells. SLC2A1-AS1 functioned as ceRNA for sponging miR-378a-3p, resulting in Glut1 overexpression in ESCC cells. MiR-378a-3p inhibited cell proliferation and invasion as well as induced apoptosis, resulting in reduced glycolysis, which was partly reversed by SLC2A1-AS1 or Glut1 overexpression in ESCC cells. Conclusion SLC2A1-AS1 plays important roles in ESCC development and progression by regulating glycolysis, and SLC2A1-AS1/miR-378a-3p/Glut1 regulatory axis may be a novel therapeutic target in terms of metabolic remodeling of ESCC patients.

Background: The treatment choice for completely resected stage IIIA/N2 non-small cell lung cancer (NSCLC) patients is still controversial now. Our study aims to identify potential prognostic factors in stage IIIA/N2 NSCLC patients with complete surgical resection and postoperative chemotherapy.Methods: In this study, we screened the stage IIIA/N2 NSCLC patients diagnosed in the Affiliated Cancer Hospital of Zhengzhou University from 2015 to 2019. Completely resected patients with postoperative chemotherapy (PCT) were enrolled. The univariate and multivariate COX proportional hazards regression analyses were used to identify the prognostic factors. The Kaplan-Meier survival curve was used to compare the disease-free survival (DFS) and overall survival (OS) in the subgroup analyses.Results: 180 patients were collected, including 142 patients with PCT treatment alone and 38 patients with postoperative radiotherapy (PORT) treatment. The median DFS was 17.8 months (95% CI: 16.5–19.1 months) and the median OS was 50.6 months (47.4–53.9 months) in all the patients. The median DFS of the PORT group was significantly longer than the PCT group (38.7 vs 16.7 months, p < 0.001). Epidermal growth factor receptor (EGFR) mutation-positive patients had a worse DFS compared with EGFR mutation-negative patients (16.8 vs 18.0 months, p = 0.032). Possible prognostic factors were evaluated through univariate COX regression analysis. The further multivariate COX regression analysis showed that patients with PORT (HR: 0.318, 95% CI: 0.185–0.547, p < 0.001), EGFR mutation-negative (HR: 0.678, 95% CI: 0.492–0.990, p = 0.044), T1 (HR: 0.661, 95% CI: 0.472–0.925, p = 0.016), and lobectomy (HR: 0.423, 95% CI: 0.191–0.935, p = 0.034), had better DFS. The only independent prognostic factor of OS was the type of surgery (p = 0.013).Conclusion: PORT might improve the DFS of stage IIIA/N2 NSCLC patients with complete surgical resection and PCT, but it cannot increase OS. Besides, EGFR mutation status, T stage, and type of surgery are possible independent prognostic factors for DFS, and type of surgery is associated with OS. These factors remain to be clarified in further studies.

Objective This study aimed to identify and evaluate the mechanism by which apoptosis and cell cycle arrest were induced by dinaciclib in lymphoma Raji cells. Methods The colony formation assay was used to detect cell proliferation of Raji cells. Cell cycle arrest and cell apoptosis were determined by flow cytometry and TUNEL assays, respectively. Protein expression related to the Raji cell state was evaluated by Western blot. The Raji/Dinaciclib drug‐resistant cell line was established, where the regulating functions of CDK1‐involved pathway were verified. In addition, the effect of dinaciclib in vivo was examined in orthotopically implanted tumors in nude mice. Results Cell apoptosis was induced, and DNA synthesis ability was decreased in a time‐dependent manner in dinaciclib‐treated lymphoma Raji cells. Furthermore, the cell cycle was found to be blocked in the G2/M Phase. Further study indicated that CDK1‐involved pathway played a key regulatory role in this process. It was revealed by cell transfection that the expression of cell cycle proteins was downregulated after treatment with dinaciclib through a CDK1‐involved pathway, which eventually led to apoptosis. Knockdown of CDK1 restored the sensitivity of the Raji/Dinaciclib cells to dinaciclib. Xenograft model of nude mice showed that dinaciclib treatment in vivo could effectively inhibit tumor growth, consistent with the experiment results mentioned before. Conclusion In this study, we clarified the mechanisms through which dinaciclib induces Raji cell apoptosis and blocks the cell cycle through a CDK1‐involved pathway, which supported that dinaciclib had potential values in the treatment of lymphoma.

Objectives: Mounting evidence has demonstrated that C-Phycocyanin (C-PC) exhibits marked antitumor activity in a wide type of tumors, such as pancreas cancer, breast carcinoma, lung cancer,...

Hypoxia is a common biological hallmark of solid cancers, which has been proposed to be associated with oncogenesis and chemotherapy resistance. The purpose of the present study was to investigate the role and underlying mechanisms of olfactomedin 4 (OLFM4) in the hypoxia-induced invasion, epithelial-mesenchymal transition (EMT), and chemotherapy resistance of non-small-cell lung cancer (NSCLC). We observed dramatically upregulated expression of OLFM4 in several NSCLC cell lines, and this effect was more pronounced in A549 and H1299 cells. In addition, our data revealed that OLFM4 expression was remarkably increased in both A549 and H1299 cells under hypoxic microenvironment, accompanied by enhanced levels of hypoxia-inducible factor (HIF)-1α protein. The HIF-1α level was elevated in response to hypoxia, resulting in the regulation of OLFM4. Interestingly, OLFM4 was a positive regulator of hypoxia-driven HIF-1α production. Moreover, depletion of OLFM4 modulated multiple EMT-associated proteins, as evidenced by the enhanced E-cadherin levels along with the diminished expression of N-cadherin and vimentin in response to hypoxia, and thus blocked invasion ability of A549 and H1299 cells following exposure to hypoxia. Furthermore, ablation of OLFM4 accelerated the sensitivity of A549 cells to cisplatin under hypoxic conditions, implying that OLFM4 serves as a key regulator in chemotherapeutic resistance under hypoxia. In conclusion, OLFM4/HIF-1α axis might be a potential therapeutic strategy for NSCLC.

Background: Esophageal cancer (EC) is one of the deadliest cancers in the world. However, the mechanism that drives the evolution of EC is still unclear. On this basis, we identified the key genes and molecular pathways that may be related to the progression of esophageal adenocarcinoma and squamous cell carcinoma to find potential markers or therapeutic targets.Methods: GSE26886 were obtained from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) among normal samples, EA, and squamous cell carcinoma were determined using R software. Then, potential functions of DEGs were determined using the Database for Annotation, Visualization and Integrated Discovery (DAVID). The STRING software was used to identify the most important modules in the protein–protein interaction (PPI) network. The expression levels of hub genes were confirmed using UALCAN database. Kaplan–Meier plotters were used to confirm the correlation between hub genes and outcomes in EC.Results: In this study, we identified 1,098 genes induced in esophageal adenocarcinoma (EA) and esophageal squamous cell carcinoma (ESCC), and 669 genes were reduced in EA and ESCC, suggesting that these genes may play an important role in the occurrence and development of EC tumors. Bioinformatics analysis showed that these genes were involved in cell cycle regulation and p53 and phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. In addition, we identified 147 induced genes and 130 reduced genes differentially expressed in EA and ESCC. The expression of ESCC in the EA group was different from that in the control group. By PPI network analysis, we identified 10 hub genes, including GNAQ, RGS5, MAPK1, ATP1B1, HADHA, HSDL2, SLC25A20, ACOX1, SCP2, and NLN. TCGA validation showed that these genes were present in the dysfunctional samples between EC and normal samples and between EA and ESCC. Kaplan–Meier analysis showed that MAPK1, ACOX1, SCP2, and NLN were associated with overall survival in patients with ESCC and EA.Conclusions: In this study, we identified a series of DEGs between EC and normal samples and between EA and ESCC samples. We also identified 10 key genes involved in the EC process. We believe that this study may provide a new biomarker for the prognosis of EA and ESCC.

N6 methyladenosine (m6A) RNA methylation regulators play an important role in the development of tumors. However, their function in esophageal cancer (EC) has not been fully elucidated. Here, we analyzed the gene expression data of 24 major m6A RNA methylation regulators from 775 patients with EC from TCGA dataset. The present study showed the aberrations of m6A regulators in genome were correlated to prognosis in human ECs. Meanwhile, 17 m6A regulators showed increased expression in EC samples, including YTHDC1, IGF2BP2, FTO, METTL14, YTHDF3, RBM15, WTAP, HNRNPA2B1, HNRNPC, ALKBH5, YTHDF2, METTL16, IGF2BP3, VIRMA, RBM15B, YTHDF1, KIAA1429, HAKAI, and ZC3H13. Among them, we found HNRNPC, YTHDC2, WTAP, VIRMA, IGF2BP3, and HNRNPA2B1 were significantly correlated to worse outcomes and advanced stage in EC. Furthermore, we showed levels of m6A regulators is correlated with the expression of Immuno-regulators (Immunoinhibitors, Immunostimulators, and MHC molecules) and immune infiltration levels in EC. Bioinformatics further confirm m6A regulators were involved in regulating RNA splicing, RNA stability, and cell proliferation. Our study showed m6A regulators are promising targets and biomarkers for cancer immunotherapy in EC.

Background: Camrelizumab (SHR1210) is a high-affinity, humanized immunoglobulin programmed cell death 1 (PD-1) monoclonal antibody. It was developed by Jiangsu Hengrui Medicine Co. Ltd. and has been approved for relapsed or refractory classical Hodgkin lymphoma patients and hepatocellular carcinoma patients in China. Apatinib is an orally administered vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor and has been approved for advanced gastric adenocarcinoma or gastroesophageal junction adenocarcinoma in China. Camrelizumab alone and its combination with apatinib have been used in the treatment of various solid cancers. Methods: We searched Embase, PubMed, and other databases with the keyword “camrelizumab” or “SHR1210,” and evaluated the safety and efficacy data of the involved studies. Adverse events (AEs) mentioned in at least two studies were summarized, including any grade and grade ≥3 treatment-related AEs. Meanwhile, efficacy data were collected, such as overall response rate (ORR), disease control rate (DCR), duration of response, 6-month progression-free survival (PFS) rate, median PFS time, 12-month overall survival rate, and median overall survival time. Results: The major AEs of camrelizumab alone were reactive cutaneous capillary endothelial proliferation, fatigue, aspartate aminotransferase increase, proteinuria, pruritus, and alanine transaminase increase. The ORR and DCR were 20.2% (95% CI: 15.1–26.6%, p = 0.000, I2 = 70.360) and 45.8% (95% CI: 39.0–52.7%, p = 0.256, I2 = 58.661), respectively. In the three studies of combination therapy, two studies were combined with apatinib and one combined with chemotherapy. For these studies, common AEs were hypertension, platelet count decrease, nausea, proteinuria, aspartate aminotransferase increase, and white blood cell count decrease. The pooled ORR, DCR, and 6-month PFS rate were 41.8% (95% CI: 29.7–54.9%, p = 0.220, I2 = 86.265), 82.4% (95% CI: 75.9–87.4%, p = 0.000, I2 = 55.207), and 56.2% (95% CI: 35.8–74.6%, p = 0.559, I2 = 79.739), respectively. Conclusion: Camrelizumab and its combination are tolerable and appear to be efficient in treating numerous solid cancers. The combination therapy appears to have better efficacy with durable toxicity. However, these remain to be shown in future studies. Besides, baseline lactate dehydrogenase, programmed cell death ligand 1 (PD-L1) expression, tumor mutation burden, and the incidence of reactive cutaneous capillary endothelial proliferation may be efficacy predictors and need to be clarified in further studies.

Background: Little is known about the morphological and molecular features of intra-thoracic myoepithelial tumors. Here, we describe a rare pulmonary myoepithelial tumor with novel TRPS1-PLAG1 fusions.Case presentation: A 30-year-old male presented with multiple lung nodules that detected by routine computed tomography (CT) scan 3 years ago. Positron emission tomography-computed tomography (PET-CT) demonstrated a well-circumscribed mass with a diameter of 3cm in the left pulmonary hilum and multiple nodules in bilateral lungs. No other extra-thoracic primary lesion and distant metastasis was found. The clinical history was not other specified. Microscopically, these lesions were well-defined, showed nodular growth pattern filling the bronchioles and alveoli. The tumor cells were epithelioid to plasmacytoid with slightly eosinophilic cytoplasm, arranged in aggregates, nests and cords. Myxoid background presented in some foci. Nuclear pleomorphism was mild and mitotic activity was not prominent. No distinct gland formation was identified. Immunostains demonstrated that the tumor cells were diffusely positive for pan-cytokeratin (AE1/AE3), CK5/6, S100, SOX10, and negative for calponin. Noticeably, a TRPS1-PLAG1 gene fusion was identified in this tumor by targeted RNA sequencing involved TRPS1 exon1 and PLAG1 exon2, this rare rearrangement was validated by fluorescence in situ hybridization (FISH) for PLAG1 break-apart probe, and 30% tumor cells showed break apart signals. Conclusions: Here we present the first case of a disseminated thoracic myoepithelial tumor with novel TRPS1-PLAG1 fusions. Targeted RNA sequencing strongly facilitates precise classification and providing opportunities for unknown fusion partner discovery, which is significant for risk stratification and development of potential therapeutic targets.

Although artists’ actions in photo retouching appear to be highly nonlinear in nature and very difficult to characterize analytically, we find that the net effects of interactively editing a mundane image to a desired appearance can be modeled, in most cases, by a parametric monotonically non-decreasing global tone mapping function in the luminance axis and by a global affine transform in the chrominance plane. This allows us to greatly simplify the existing CNN methods for mimicking the artists in photo retouching, and design a new artful image regeneration network (AIRNet). The objective of AIRNet is to learn the image-dependent parameters of the luminance tone mapping function and the affine chrominance transform, rather than learning the end-to-end pixel level mapping as in the standard practice of current CNN methods for image restoration and enhancement. The proposed new approach reduces the complexity of the neural network by two orders of magnitude, and as a side benefit, it also improves the robustness and the generation capability at the inference stage.

To explore the genetic basis for a patient with Leydig cell hypoplasia.Whole exome sequencing was used to detect genetic variants in the patient. Suspect variants were verified by PCR and Sanger sequencing of the family members.The patient was found to carry two novel variants, namely c.265AT (p.Ile189Leu) and c.422TC (p.Val141Ala), of the luteinizing hormone receptor gene (LHCGR), where were respectively inherited from her father and mother. Upon prenatal diagnosis, the fetus was found to be a heterozygous carrier of the c.265AT (p.Ile189Leu) variant.The compound heterozygous variants of c.265AT (p.Ile189Leu) and c.422TC (p.Val141Ala) of the LHCGR gene probably underlie the Leydig cell hypoplasia in the patient.

Objective: The present study aims to investigate microRNAs (miRNAs) and messenger RNAs (mRNAs) associated with breast cancer, and to have a better understanding of the mechanism of miRNAs in breast cancer using bioinformatics tools. Methods: Microarray analysis was performed to predict differentially expressed miRNAs related to breast cancer, followed by prediction and verification of target genes. Human breast cancer cells were transfected and divided into Blank group, NC group, miR-21-5p mimic group, miR-21-5p inhibitor group and siRNA-MAPK10 group. RT-qPCR and Western blot analysis were used to detect mRNA and protein expressions of MAPK10 in tissues and transfected cells, MTT assay, scratch test and Transwell assay for detection of the proliferation, migration and invasion, and Annexin-V-R-PE assay for apoptosis of different cell lines. Results: Highly expressed miR-21-5p and lowly expressed MAPK10 were selected for subsequent experiments, according to the microarray analysis. RT-qPCR showed that the expression of MAPK10 in breast cancer tissues was significantly lower than that in adjacent tissues, while it was reciprocal in expression of miR-21. miR-21-5p negatively regulated MAPK10. The expression of MAPK10 reduced in response to miR-21-5p mimic treatment. Compared with the Blank and NC groups, the proliferation, migration, invasion and metastasis of breast cancer cells decreased, and the apoptosis of breast cancer cells increased in the miR-21-5p inhibitor group and siRNA-MAPK10 group, while it was reciprocal in the miR-21-5p mimic group. Conclusion: MiR-21 promotes the proliferation, migration and invasion and inhibits the apoptosis of breast cancer cells by inhibiting MAPK10.

To study the effects of Pim-3 on lung adenocarcinoma A549 cells. A549 cells were divided into an untreated group (without any treatment), a scramble siRNA group (transfected with control siRNA), and a Pim-3-deficient group (transfected with Pim-3 siRNA).Pim-3-deficient cells are the experimental sample, whereas scramble siRNA and untreated cells are the corresponding negative controls. Western blotting was performed to detect the expression levels of Pim-3 protein, the phosphorylation of signal transducer and activator of transcription 3 (STAT3), and the expression levels of downstream target genes (p21, cyclin D1, Bcl-2, and Bax). Flow cytometry was performed to analyze cell cycle and apoptosis.In the Pim-3-deficient group, Pim-3 was downregulated, the STAT3 phosphorylation level decreased, the levels of cyclin D1 and Bcl-2 decreased, but the levels of p21 and Bax increased. Meanwhile, cell proliferation was significantly inhibited (The downregulation of Pim-3 was closely related to the activation status of the lung STAT3 signaling pathway, mediated cell proliferation inhibition and induced apoptosis.

Chemoresistance is a critical obstacle to the treatment of hepatocellular carcinoma (HCC). The mechanisms underlying resistance to doxorubicin, cisplatin, and 5-fluorouracil involve p53 and P-glycoprotein (P-gp). p53 plays a role in cell growth; therefore, resistance mechanisms involve chemotherapy-induced apoptosis and p53 mutation and inactivation. P-gp is an energy-dependent drug efflux pump regulated by p53. Its role in drug resistance has provided new insights into the mechanisms underlying the involvement of p53 and P-gp in chemoresistance and may alter our traditional understanding of p53 and P-gp function. This review outlines the roles and principal mechanisms of p53 and P-gp mediated chemoresistance in HCC.

// Yunhui Qu 1, 2, * , Hongtao Liu 3, * , Xinquan Lv 1 , Yuqiong Liu 1 , Xiaojuan Wang 1 , Min Zhang 1 , Xiaqing Zhang 3 , Yuenan Li 3 , Qianqian Lou 3 , Shenglei Li 1 and Huixiang Li 1 1 Department of Pathology, School of Basic Medical Sciences, Zhengzhou University and The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450001, Henan, P.R. China 2 Clinical Laboratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450001, Henan, P.R. China 3 Laboratory for Cell Biology, College of Life Sciences of Zhengzhou University, Zhengzhou, 450001, Henan, P.R. China * These authors contributed equally to this work Correspondence to: Huixiang Li, email: lhx20170220@126.com Keywords: microRNA-16-5p, breast carcinoma, HIF-α, VEGFA, tumor growth Received: March 03, 2017 Accepted: August 07, 2017 Published: August 23, 2017 ABSTRACT MicroRNAs (miRNAs), a class of small noncoding RNA molecules, can manipulate the expressions of endogenous tumor-related genes, and are implicated in the development and progression of a wide type of tumors. In this study, the investigation from real-time quantitative PCR revealed that miRNA-16-5p was downregulated in breast carcinoma tissues and cells, coupled with the elevations of HIF-α and VEGFA protein expressions, compared with normal tissues. Lentiviral armed with miR-16-5p markedly increased the miR-16-5p levels in MCF-7 and MDA-MB-231 cells, compared to blank and NC groups, and miR-16-5p overexpression significantly inhibited the proliferation and colony formation in MCF-7 and MDA-MB-231 cells. Besides, miR-16-5p upregulation markedly induced apoptosis and reduced invasion ability in MCF-7 and MDA-MB-231 cells. Notably, VEGFA was direct target of miR-16-5p. Stepwise investigation from in vitro and in vivo experiments demonstrated that miR-16-5p overexpression suppressed tumor growth and reduced HIF-α and VEGFA expressions in breast carcinoma cells and nude mice tumor tissues. These findings provide novel insights into molecular mechanism involved in the roles of miR-16-5p in tumor development and progression of breast carcinoma, and thus manipulation of miR-16-5p may be a novel potential therapeutic target for future therapies of the patients with breast carcinoma.

Hematopoietic progenitor kinase 1 (HPK1) belongs to the mitogen activated protein kinase kinase kinase kinase (MAP4K) family of serine/threonine kinases, which have been associated with the incidence and progression of a variety of gastrointestinal malignant tumors in humans. However, the potential association between HPK1 expression and breast cancer, particularly invasive ductal carcinoma-not otherwise specified (IDC-NOS) development, has not yet been examined. To address this gap, the present study aimed to evaluate HPK1 expression in IDC-NOS samples and to determine a relationship with clinical prognostic indicators, such as the expression levels of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), as well as overall survival of the patients with IDC-NOS. HPK1 mRNA and protein expression in samples from 148 patients with IDC-NOS were detected using immunohistochemistry, western blotting and reverse transcription-quantitative polymerase chain reaction. A total of 54 out of 148 (36.5%) samples were HPK1-positive, and 100 out of 148 (67.6%) were ER-positive. Of the latter, 28% (28/100) were HPK1-positive, and a significant negative association of HPK1 expression with ER positivity was observed (P=0.002; r=−0.254). In addition, 43.2% (64/148) and 32.4% (48/100) of IDC-NOS tissues were PR- or HER2-positive, respectively; however, neither indicator correlated with HPK1 (P=0.109 and P=0.558, respectively). HPK1 expression, axillary lymph node metastasis and tumor-node-metastasis (TNM) stage were identified as independent factors of overall survival (OS) in the ER-positive group (P

// Shenglei Li 1, * , Hongtao Liu 2, * , Changying Diao 1 , Xiaohui Wang 1 , Ming Gao 3 , Zongming Li 4 , Lijie Song 3 , Xianzheng Gao 1 , Jing Han 1 , Feng Wang 3 , Wencai Li 1 and Xinwei Han 4 1 Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 50000, China 2 Laboratory for Cell Biology, College of Life Sciences of Zhengzhou University, Zhengzhou, Henan, 450001, China 3 Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450000, China 4 Department of Interventional Therapy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450000, China * These authors have contributed equally to this work Correspondence to: Feng Wang, email: wangangvv@yeah.net Xinwei Han, email: chenyueqinms@163.com Keywords: esophageal cancer, surgery, adjuvant therapies, chemotherapy, radiotherapy Received: September 09, 2016 Accepted: February 20, 2017 Published: March 14, 2017 ABSTRACT This network meta-analysis was conducted to assess whether the efficacy of surgery with adjuvant therapies, including radiotherapy (RT+S), chemotherapy (CT+S), and chemoradiotherapy (CRT+S) have better performance in esophageal cancer treatment and management. PubMed and EMBASE were used to search for relevant trials. Both conventional pair-wise and network meta-analyses were carried out. The surface under the cumulative ranking curve (SUCRA) was used to rank interventions based on the efficacy of the treatment method. As for 3-year overall survival (OS), CRT+S showed the highest efficacy (CRT+S vs. surgery: HR=0.81, 95% CrI =0.73-0.90; CRT+S vs. CT+S: HR=0.82, 95% CrI =0.70-0.95; CRT+S vs. RT+S: HR=0.77, 95% CrI =0.62-0.95). For disease-free survival, CRT+S showed efficacy over CT+S ((HR =0.70, 95% CrI =0. 59-0.83). In conclusion, CRT+S showed a better performance for survival outcomes and ranks best among all therapies. The results of our study can provide guidance for medical decisions and treatment options that may help clinical practitioners improve the efficacy of EC treatment.

Esophageal cancer (EC) is one of the most common cancers with poor survival in the world. Nowadays, a generous number of clinical trials are underway on the use of immunotherapy in EC patients, especially the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors. However, only a few patients could benefit from single-agent therapy. Others need combination therapies to enhance the response rate and survival. In this review, we focus on PD-1/PD-L1 inhibitors and its combination options in EC patients. We also summarized the potential predictive biomarkers for PD-1/PD-L1 inhibitors treatment.

Dysregulation of mTORC1/mTORC2 pathway is observed in many cancers and mTORC1 inhibitors have been used clinically in many tumor types; however, the mechanism of mTORC2 in tumorigenesis is still obscure. Here, we mainly explored the potential role of mTORC2 in esophageal squamous cell carcinoma (ESCC) and its effects on the sensitivity of cells to mTOR inhibitors. We demonstrated that RICTOR, the key factor of mTORC2, and p-AKT (Ser473) were excessively activated in ESCC and their overexpression is related to lymph node metastasis and the tumor-node-metastasis (TNM) phase of ESCC patients. Furthermore, we found that mTORC1/ mTORC2 inhibitor PP242 exhibited more efficacious anti-proliferative effect on ESCC cells than mTORC1 inhibitor RAD001 due to RAD001-triggered feedback activation of AKT signal. Another, we demonstrated that down-regulating expression of RICTOR in ECa109 and EC9706 cells inhibited proliferation and migration as well as induced cell cycle arrest and apoptosis. Noteworthy, knocking-down stably RICTOR significantly suppresses RAD001-induced feedback activation of AKT/PRAS40 signaling, and enhances inhibition efficacy of PP242 on the phosphorylation of AKT and PRAS40, thus potentiates the antitumor effect of RAD001 and PP242 both in vitro and in vivo. Our findings highlight that selective targeting mTORC2 could be a promising therapeutic strategy for future treatment of ESCC., Graphical abstract This study demonstrated that mTORC2 subunit, RICTOR, and p-AKT (Ser473) have hyperactivity in esophageal squamous cell carcinoma (ESCC) and promotes its development. Moreover, down-regulation of RICTOR can improve the sensitivity of ESCC cells to the pan-mTOR inhibitor PP242 as well as mTORC1 inhibitor RAD001.Image 1

Laryngeal squamous cell carcinoma (LSCC) is one of the most common subtypes of head and neck malignancies worldwide. Long intervening/intergenic noncoding RNAs (LINCRNAs) have been recently implicated in various biological processes that take place in the setting of laryngeal cancer, but the regulatory role of LINC00319 in LSCC remains largely unknown. The current study aimed to elucidate the regulatory effect of LINC00319 on the development and progression of LSCC via high-mobility group box 3 (HMGB3). Microarray-based analysis was initially conducted to identify differentially expressed long noncoding RNAs, after which the expression of LINC00319 and HMGB3 in LSCC tissues and cells was determined accordingly. CD133+CD144+ TU177 cells were subsequently isolated and transfected with LINC00319 overexpression vector (oe-LINC00319), short hairpin RNA (sh)-LINC00319, sh-HMGB3, sh-E2F transcription factor 1 (E2F1), and oe-E2F1, as well as their corresponding controls. The proliferative, invasion, self-renewal, and tumorigenic abilities of CD133+CD144+ TU177 cells were then evaluated. Our in vitro findings were further confirmed following subcutaneous injection of cells expressing the corresponding plasmids into nude mice. LINC00319 and HMGB3 expressions were elevated in LSCC cells and tissues. LINC00319 increased HMGB3 expression by recruiting E2F1. Furthermore, the stimulatory role of LINC00319 on the proliferation, invasion, self-renewal ability, and tumorigenicity of CD133+CD144+ TU177 cells was achieved by upregulating HMGB3 via recruitment of E2F1. The in vitro findings were also confirmed by in vivo experiments. Taken together, these data show that downregulating LINC00319 in CD133+CD144+ TU177 cells may serve as a potential anticancer regimen by inhibiting the proliferation and invasion of cancer stem cells in LSCC., Cancer: An RNA promotes throat cancer progression The identification of a cellular RNA that drives tumor proliferation and invasion could lead to new treatments for a common form of throat cancer that often presents with a grim prognosis. With early diagnosis, laryngeal squamous cell carcinoma (LSCC) can be treated effectively, but patients with advanced or recurrent disease have a 5-year survival rate of just 50%. Researchers led by Shenglei Li and Wencai Li at Zhengzhou University in China have found that increased production of an RNA known as LINC00319 is linked with worse outcomes for LSCC patients. This RNA does not encode a protein, but instead regulates expression of other genes that allow reservoirs of ‘cancer stem cells’ associated with tumor progression to flourish. Based on these findings, the researchers propose that drugs targeting LINC00319-regulated cellular processes could offer useful LSCC therapeutics.

Breast cancer is the most common cancer affecting women and one of the leading causes of cancer-related deaths worldwide. In existing studies, some long non-coding RNAs (lncRNAs) are considered to have important regulatory roles in the development of cancers. However, the pathogenic significance of LINC00511 in breast cancer is unclear. In this study, LINC00511 was significantly up-regulated in breast cancer, and its expression level was correlated to poor prognosis of patients with breast cancer. To further study the role of LINC00511 in breast cancer, we knocked down the expression of LINC00511 using siRNAs. Cells transfected with siRNA-2 proliferated, and its metastasis was suppressed. RNA-seq analysis revealed 182 potential targets for LINC00511. The in-silico analysis revealed that differently expressed genes were closely related to signaling mediated by p38-alpha and p38-beta. Subcellular localization showed that LINC00511 was mainly located in the cytoplasm, and knocking down the LINC00511 gene could down-regulate the expression of MMP13. Using bioinformatics analysis combined with dual-luciferase report assay, we finally determined that miR-150 was the direct target of LINC00511. The dual-luciferase report assays also showed that MMP13 was the target of miR-150. LINC00511 knockdown significantly reduced MMP13 protein levels, and miR-150 gene knockdown significantly rescued the down-regulation of MMP13 caused by LINC00511 gene silencing. Moreover, silencing MMP13 and overexpression of miR-150 could reduce the proliferation of breast cancer cells. In conclusion, our data show that LINC00511 is a breast cancer promoter, and the LINC00511/miR-150/MMP13 axis may be a new therapeutic strategy for breast cancer patients.

Increasing evidence has demonstrated that histone deacetylase 2 (HDAC2) participates in the regulation of a variety of biological processes in numerous tumors. However, the potential role of HDAC2 in the development and progression of esophageal squamous cell carcinoma (ESCC) remains elusive. Immunohistochemistry was utilized to detect the expression of HDAC2, Cell Counting Kit-8 was used to determine the cell proliferation, and flow cytometry was employed to investigate cell cycle and cell apoptosis. Finally, western blotting was employed to detect the protein expression of cyclin D1, p21, B cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax). The present study found that expression of HDAC2 protein in ESCC tissues was significantly increased compared with atypical hyperplasia tissues and normal esophageal mucosa (P0.05), but was closely associated with the histological grade, invasion depth, tumor-node-metastasis stage and lymph node metastasis, respectively (all P