miR-375 inhibits Helicobacter pylori-induced gastric carcinogenesis by blocking JAK2–STAT3 signaling

Abstract

Gastric cancer remains the second leading cause of cancer-related deaths worldwide. Although Helicobacter pylori (H. pylori) is considered to be a critical risk factor, the molecular mechanisms underlying H. pylori-induced gastric carcinogenesis are still poorly defined. Recently, accumulating studies have revealed that microRNAs play key roles in development, differentiation, immune regulation, and even carcinogenesis. This study was performed to explore the mechanism of microRNA-375 (miR-375) in H. pylori promotion of gastric carcinogenesis. It was shown that miR-375 was down-regulated in response to H. pylori infection in gastric epithelial cell lines; this finding was quite opposite to the expression patterns of pro-inflammatory cytokines observed in a co-culture cell model. Moreover, the ectopic expression of miR-375 aggravated cell proliferation and migration. It was further observed that Janus kinase 2 (JAK2) was a bona fide target of miR-375 and further activated signal transducer and activator of transcription 3 (STAT3) and other downstream target molecules. Both gain-of-function and loss-of-function experiments showed that decreased miR-375 expression could mimic the oncogenic effects of the JAK2-STAT3 pathway. In addition, pretreatment with siRNAs targeting JAK2 prevented gastric epithelial cells from increasing proliferation and migration even in response to H. pylori infection. For the first time, our results demonstrate that the JAK2-STAT3 pathway regulated by miR-375 is involved in H. pylori-induced inflammation; this pathway promotes neoplastic transformation by affecting the expression of BCL-2 and TWIST1, hence offering a potential therapeutic target for inflammation-related cancers, especially those related to H. pylori.

The Effect of MicroRNA-375 Overexpression, an Inhibitor of Helicobacter pylori-Induced Carcinogenesis, on lncRNA SOX2OT

“…One proposed mechanism has been called perigenetic pathway involves enhancement of the transformed host cell phenotype by means of alteration in gene expression without the need for additional mutations in tumor suppressor genes (26). The miR-375 is one of the miRNAs regulating inflammation and carcinogenetic processes induced by H. pylori acts through perigenetic pathway (19, 27). …”

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

“…Emerging evidence demonstrates that deregulated microRNAs (miRNAs) are involved in many processes of tumor progression, such as tumor initiation, cell proliferation, apoptosis, invasion, metastasis, angiogenesis, and epithelial-to-mesenchymal transition [5]. We and other groups have found that a number of miRNAs, including miR-375 [6], miR-204 [7], and miR-126 [8], were down-regulated in GC. In contrast, long noncoding RNAs (lncRNAs), tentatively defined as ncRNAs more than 200 nt in length, are also known to play key roles in cancer development and aberrant expression of lncRNAs have been functionally associated with GC [9].…”

MicroRNA-125b targeted STAT3 to inhibit laryngeal squamous cell carcinoma cell growth and motility

“…In gastric cancer, miR-874 targeted the STAT3/vascular endothelial growth factor A signaling pathway and functioned as a tumor suppressor (44). miR-375 was involved in helicobacter pylori-induced gastric tumorigenesis by inhibiting the activity of JAK2/STAT3 signaling (45). However, there are no studies about the regulation of STAT3 by miRNA in LSCC.…”