Role Of Bile Acid Membrane Receptor TGR5 In Intestinal Inflammation And Tumor Characteristics

TGR5,a G protein-coupled bile acid membrane receptor,is well known for its roles in the regulation of glucose metabolism,bile acid enterohepatic circulation and energy homeostasis.Inflammatory bowel disease（IBD）is a nonspecific chronic inflammatory disease of the gut.Colorectal cancer（CRC）is the third most common cancer worldwide and the second highest mortality rate of all cancers.More and more studies have shown that TGR5 is important in inflammation and cancer,but the role of TGR5 in enteritis and bowel cancer is unclear.Here we demonstrate that TGR5 is a negative regulator of NF-κB and STAT3-mediated intestinal inflammation and tumor properties.In this study,the TCGA online analysis website was used to analyze the expression of TGR5 in human colorectal cancer and normal tissues,and it was found that the expression of TGR5 was obviously lower in cancer tissues than in normal tissues.QRT-PCR was further performed on 30 pairs of human colorectal cancer and adjacent normal tissues in the laboratory.The results were similar to the database,and the expression of TGR5 was significantly down-regulated in tumor tissues.According to ROC curve analysis,TGR5 has potential as a biomarker for clinical diagnosis of colorectal cancer.In a dextran sodium sulfate（DSS）-induced ulcerative colon inflammation model.TGR5^-/-mice exhibited more severe inflammatory response compared with wide-type（WT）mice.In a lipopolysaccharide（LPS）-induced inflammation model,activation of TGR5inhibited LPS-induced phosphorylation of IκBαand STAT3 in colon tissue of WT mice and down-regulated the expression of inflammatory genes.In cell experiments,TGR5 agonists can inhibit the proliferation and migration of colorectal cancer cells.Further research revealed that activation of TGR5 can inhibit IκBαand STAT3 phosphorylation,NF-κB transcription activity,NF-κB and STAT3 target gene expression.Activation of TGR5 can inhibit the inflammatory response process during enteritis and bowel cancer by antagonizing NF-κB and STAT3 signaling,and inhibit the progression of enteritis and bowel cancer.In addition,TGR5 agonists can down-regulate the expression of lnc RNA MIR210HG,and knockdown of MIR210HG can also antagonize NF-κB and STAT3 signaling pathways.Therefore,we believe that TGR5 may antagonize NF-κB and STAT3 signaling partly by down-regulating MIR210HG.This study demonstrated TGR5 as a negative regulator of inflammation and tumor properties that may serve as a potential biomarker and therapeutic target for enteritis and bowel cancer.