microRNA-365 inhibits YAP through TLR4-mediated IRF3 phosphorylation and thereby alleviates gastric precancerous lesions

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.

Identification of serum microRNAs as potential diagnostic biomarkers for detecting precancerous lesions of gastric cancer

“…Of those, miR‐421 , 19 miR‐19a‐3p , and miR‐483‐5p 25 showed clinical significance, especially in GC cases. Another miRNA, miR‐365 , inhibited the progression of precancerous lesions in the stomach 20 . These reports differ from our current study on the following points.…”

“…Another miRNA, miR-365, inhibited the progression of precancerous lesions in the stomach. 20 These reports differ from our current study on the following points. They used miRNAs that were already shown In (E), we used the TCGA database to compare the expression of the two miRNAs in GC tissue and normal tissue.…”

“…Another miRNA, miR‐365 , inhibited the progression of precancerous lesions in the stomach. 20 These reports differ from our current study on the following points. They used miRNAs that were already shown to be highly expressed in early and advanced GC, and they confirmed that those miRNAs are also highly expressed in sera from precancerous lesions.…”

“…An association between GC and various miRNAs has been shown 17,18 . There have been several reports on miRNA expression in precancerous lesions of GC 19,20 . However, the results have not been verified sufficiently, and there are no reports of comprehensive analysis using microarrays.…”

LncRNA H19-rich extracellular vesicles derived from gastric cancer stem cells facilitate tumorigenicity and metastasis via mediating intratumor communication network

“…In addition, YAP contributes to promotion of stem cell maintenance [ 10 ]. Notably, downregulation of YAP results in a decline of CDX2 expression in GC cells [ 43 ]. CDX2 is abundant in GC tissues and cells, which augments the proliferative, migrating, and invasive properties of GC cells [ 32 ].…”