microRNA-365 inhibits YAP through TLR4-mediated IRF3 phosphorylation and thereby alleviates gastric precancerous lesions
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PRIMARY RESEARCH
Cancer Cell International Open Access
microRNA‑365 inhibits YAP through TLR4‑mediated IRF3 phosphorylation and thereby alleviates gastric precancerous lesions Tianqi Zhang†, Kunpeng Zhang†, Kaiyue Ji, Cuiping Zhang, Yueping Jiang, Qi Zhang, Zibin Tian, Xinyu Wang, Mengyuan Zhang and Xiaoyu Li*
Abstract Background: Gastric carcinoma (GC) is currently one of the most common malignant tumors of the digestive system, and gastric precancerous lesions play a vital role in studying the mechanism of GC. Multiple microRNAs (miRNAs) have been documented to be potential biomarkers to indicate progression of gastric precancerous lesions. In this study, we explained the anti-cancer effect of miR-365 in gastric precancerous lesions via regulation of the TLR4/IRF3/ YAP/CDX2 axis. Methods: miR-365, TLR4, CDX2 and IPF3 expression was determined in GC and atrophic gastritis tissues and cells. After transfection of shRNA and overexpression plasmids, in vitro experiments detected the alteration of cell viability, apoptosis and inflammatory factors. Bioinformatics analysis, Co-IP and dual luciferase reporter gene assay were conducted to evaluate the binding between miR-365 and TLR4 as well as IRF3 and YAP. Rat models were established to explore the effect of the miR-365 and TLR4 on gastric precancerous lesions. Results: miR-365 was poorly expressed in GC and atrophic gastritis tissues and GC cell lines, while TLR4, CDX2 and IRF3 were overexpressed. Of note, miR-365 was indicated to target TLR4 and thereby suppressed cancer progression and increased hemoglobin content. Interestingly, silencing of TLR4 was accompanied by decreased IRF3 phosphorylation and reduced expression with less binding between CDX2 and IRF3. Downregulation of YAP resulted in declined CDX2 expression in cancer cells. Moreover, the inhibitory role of miR-365 was further confirmed in animal models. Conclusion: Taken together, miR-365-mediated TLR4 inhibition reduces IRF3 phosphorylation and YAP-mediated CDX2 transcription to impede progression of gastric precancerous lesions. Keywords: MicroRNA-365, TLR4, IRF3, YAP, CDX2, Gastric precancerous lesions
*Correspondence: [email protected] † Tianqi Zhang and Kunpeng Zhang are co-first authors Department of Gastroenterology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Shinan District, Qingdao 266000, Shandong, People’s Republic of China
Background Gastric cancer (GC), the most common gastrointestinal malignant tumor, is primarily characterized by anorexia, dyspepsia, weight loss and abdominal pain [1]. H pylori infection and other various factors such environmental factors induce the pathogenesis of GC [2]. However, despite improvements in surgery and chemotherapy for GC, the 5-year overall survival rate is still unsatisfactory
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