Abstract
BackgroundGastric 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.MethodsmiR-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.ResultsmiR-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.ConclusionTaken together, miR-365-mediated TLR4 inhibition reduces IRF3 phosphorylation and YAP-mediated CDX2 transcription to impede progression of gastric precancerous lesions.
Highlights
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
The starBase database further determined that miR-365 was downregulated in GC (Fig. 1a), but miR-365 has rarely been studied in gastric precancerous lesions
Cell viability and apoptosis were detected by CCK-8 assay and flow cytometry (Fig. 7b, c), and the results demonstrated that the cell viability upon sh-TLR4 + oe-NC transfection was significantly reduced, and apoptosis was significantly elevated (p < 0.05) while sh-TLR4 + oe-CDX2 transfection showed a reverse trend (p < 0.05)
Summary
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. We explained the anti-cancer effect of miR-365 in gastric precancerous lesions via regulation of the TLR4/IRF3/ YAP/CDX2 axis. Gastric cancer (GC), the most common gastrointestinal malignant tumor, is primarily characterized by anorexia, dyspepsia, weight loss and abdominal pain [1]. GC is usually accompanied by gastric precancerous lesions that are more prone to become cancerous in pathology. MiR-365 was predicted to target TLR4 and inhibit its expression by in silico analysis in the present study
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