Helicobacter pylori infection related long noncoding RNA (lncRNA) AF147447 inhibits gastric cancer proliferation and invasion by targeting MUC2 and up-regulating miR-34c.

Long non-coding RNAs (lncRNAs) were shown to play critical roles in cancer biology. We investigated whether H. pylori infection could promote gastric cancer by regulating lncRNAs expression. Differentially expressed lncRNAs between H. pylori positive and negative tissues were identified by microarray and validated by qRT-PCR. Our results indicated that H. pylori positive tissues have a specific profile of lncRNAs. Cell biological assays with siRNA-mediated knockdown or lentivirus vector-mediated over-expression were performed to probe the functional relevance of the lncRNAs. We identified an lncRNA-AF147447 decreased expressed by H. pylori infection, which can inhibit GC proliferation and invasion in vitro and in vivo, act as a tumor suppressor in the development of H. pylori induced GC. LncRNA AF147447 could repress MUC2 expression by direct binding or increasing miR-34c expression. We also found that transcription factor E2F1 could be recruited to lncRNA AF147447 promoter by RNA immunoprecipatation and RNA pull down assays. These findings support a role of lncRNA AF147447 in tumor suppression. This discovery contributes to a better understanding of the importance of the deregulated lncRNAs by H. pylori infection and provides a rationale for the potential development of lncRNA-based targeted approaches for the treatment of H. pylori-related gastric cancer.

Incretin-Based Therapy and Risk of Pancreatic Cancer in Patients with Type 2 Diabetes Mellitus: A Meta-analysis of Randomized Controlled Trials.

INTRODUCTION: The present study aims to evaluate the risk of pancreatic cancer with incretin-based therapy among patients with type 2 diabetes mellitus (T2DM). METHODS: We searched EMBASE, MEDLINE, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov for eligible studies published up to March 06 2016. This meta-analysis includes all studies reporting adverse events of pancreatic cancer with use of incretin-based therapies compared with placebo or non-incretin anti-diabetic drugs in patients with T2DM. We used fixed-effect model to compare pooled relative risk (RR) with related 95% confidence intervals (CI). RESULTS: A total of 159 randomized trials were identified. Out of these, 135 studies were excluded as pancreatic cancer occurrence had not been included as an end point. The remaining 24 trials enrolling 47,904 participants were further assessed. Overall, no increased risk of pancreatic cancer were detected in association with incretin-based treatment (RR = 0.7, 95% CI 0.37-1.05). The incidence of pancreatic neoplasm was even lower among incretin-based groups than controls (RR = 0.50, 95% CI 0.29-0.87) in trials with duration more than 104 weeks. There was even decreased risk of pancreatic cancer within groups paralleled by incretin-matched placebos (RR = 0.55, 95% CI 0.32-0.93) than by non-incretin anti-diabetic drugs. Neither monotherapy (RR = 0.62, 95% CI 0.38-1.01) nor combination regimen (RR = 0.92, 95% CI 0.45-1.90) of incretin mimetics increased the risk of pancreatic cancer. CONCLUSION: This meta-analysis shows that incretin-based therapies are not associated with increase in the risk of pancreatic cancer. Interestingly, subgroup analyses suggested lower risk of pancreatic cancer in incretin groups than placebo in long-term studies (>104 weeks). Considering the inconsistent results among randomized trials and previous epidemiological investigations, more such studies should be conducted to clarify the existence or non-existence of this association. FUNDING: This work was supported by grants from the National Natural Science Foundation of China (Nos. 81270476 and 81470830).

Clinical role of circulating miR-223 as a novel biomarker in early diagnosis of cancer patients.

BACKGROUND: Current diagnostic procedures of cancers are invasive and non-specific. MicroRNAs (miRNAs) have become promising molecular markers for gastric cancer (GC) predication. However, there have been inconsistencies in the literature regarding the suitability of circulating miRNAs for early detection of cancers. METHODS: We performed a comprehensive meta-analysis to integrate an evaluation index for diagnostic accuracy of miR-223 in diagnosing cancer patients. Furthermore, we conducted an independent validation set of 50 gastric cancer patients and 50 healthy controls comparing miR-223 expression. We also analyzed miR-223 expression in vitro. RESULTS: A total of 11 studies met the inclusion criteria and therefore included in this meta-analysis. We found that miR-223 yielded a pooled area under ROC curve (AUC) of 0.89 (sensitivity: 81%, specificity: 84%) in discriminating cancer from controls. In our validation test, plasma miR-223 levels in GC patients were significantly higher than that in healthy controls (P<0.01). ROC curve analysis showed that AUC was 0.812 with a sensitivity of 70% and specificity of 80%. Moreover, the expression trend of miR-223 in plasma samples was in accordance with that of tissue and cell samples. CONCLUSION: Current evidences suggested that plasma miR-223 could be a reliable and non-invasive biomarker for cancer diagnosis. Further large-scale prospective studies are necessary to validate their potential applicability in human cancer diagnosis.

MiR-141 Inhibits Gastric Cancer Proliferation by Interacting with Long Noncoding RNA MEG3 and Down-Regulating E2F3 Expression.

BACKGROUND: MiR-141 and long noncoding RNA MEG3 have been independently reported to be tumor suppressor genes in various cancers. However, their expression has never been previously associated with gastric cancer (GC). AIMS: To investigate the interaction of miR-141 and MEG3 in GC. METHODS: QRT-PCR was used to detect miR-141, MEG3, and E2F3 in gastric tissues and cells. CCK-8 and flow cytometry analysis were used to detect cell functions. Western blot and luciferase activity were used to identify E2F3 as one of the direct targets of miR-141. RESULTS: We found that expression of both miR-141 and MEG3 was significantly reduced in GC compared with levels in matched nonmalignant tissues. Positive correlation between miR-141 and MEG3 was found in both tumor tissues and control tissues. Furthermore, the over-expression of either miR-141 or MEG3 in 7901 and MKN45 cells inhibited cell proliferation and cell cycle progression and promoted cell apoptosis. E2F3 was identified as a target of miR-141, and its inhibition significantly reduced MEG3 expression. E2F3 expression was also found to be negatively associated with both MEG3 and miR-141. E2F3 over-expression partly reversed the changes caused by transfection of miR-141 mimic, and inhibition of miR-141 or MEG3 overrides MEG3- or miR-141-induced modulation of cell growth in GC. CONCLUSIONS: These findings together suggested that miR-141 could be interacting with MEG3 and targeting E2F3, and these factors may play important anti-tumor effects in GC pathogenesis and provide therapeutic targets in the clinics.

MiR-223 promotes the cisplatin resistance of human gastric cancer cells via regulating cell cycle by targeting FBXW7.

BACKGROUND: Increasing evidence showed that miRNAs serve as modulators of human cancer, either as oncogene or tumor suppressors. Cisplatin resistance is the most common cause of chemotherapy failure in gastric cancer (GC). However, the roles of miRNAs in cisplatin resistance of GC remain largely unknown. The aim of the study was to identify a novel miRNA/gene pathway that regulates the sensitivity of GC cells to cisplatin. METHODS: In this study, we chose miR-223 by qRT-PCR analysis, the most significantly up-regulated miRNA in GC, to investigate its formation of DDP-resistant phenotype of GC cells and possible molecular mechanisms. RESULTS: We found that miR-223 was most significantly up-regulated miRNA in DDP-resistant GC cells compared with parental GC cells. Besides, its expression was also significantly up-regulated in GC tissues. FBXW7 was identified as the direct and functional target gene of miR-223. Overexpression of FBXW7 could mimic the effect of miR-223 down-regulation and silencing of FBXW7 could partially reverse the effect of miR-223 down-regulation on DDP resistance of DDP-resistant GC cells. Besides, miR-223 and FBXW7 could affect the G1/S transition of cell cycle by altering some certain cell cycle regulators. Furthermore, miR-223 was found to be significantly up-regulated in H. pylori infected tissues and cells, suggesting that H. pylori infection may lead to GC development and DDP resistance. CONCLUSIONS: Our findings revealed the roles of miR-223/FBXW7 signaling in the DDP resistance of GC cells and targeting it will be a potential strategic approach for reversing the DDP resistance in human GC.

Down-regulation of miR-203 induced by Helicobacter pylori infection promotes the proliferation and invasion of gastric cancer by targeting CASK.

Several microRNAs (miRNA) have been implicated in H. pylori related gastric cancer (GC). However, the molecular mechanism of miRNAs in GC has not been fully understood. In this study, we reported that miR-203 is significantly down-regulated in H. pylori positive tissues and cells and in tumor tissues with important functional consequences. Ectopic expression of miR-203 dramatically suppressed cell proliferation and invasion. We found that miR-203 strongly reduced the expression of CASK oncogene in GC cells. Similar to the restoring miR-203 expression, CASK down-regulation inhibited cell growth and invasion, whereas CASK over-expression rescued the suppressive effect of miR-203. These results can also be found in nude mice. In clinical specimens, CASK was over-expressed in tumors and H. pylori positive tissues and its mRNA levels were inversely correlated with miR-203 expression. Taken together, our results indicated that miR-203 functions as a growth-suppressive miRNA in H. pylori related GC, and that its suppressive effects are mediated mainly by repressing CASK expression.