The Role And Mechanism Of TGR5 In Lung Cancer Cell

The bile acid receptor TGR5,also known as G protein-coupled bile acid receptor 1(GPBAR1)or bile acid membrane receptor(M-BAR),is epressed in many organs of the human body.TGR5 as a metabolic reglator is widely involved in the energy balance,bile acid homeostasis and glucose metabolism.The latest research shows that the function of TGR5 is not only metabolic reglation,but also participates in physiologic activities such as inflammatory reaction,liver regeneration and cancer occurrence and development.As a major cell survival signal,NF-?B is involved in the process of canceration and the resistance of cancer cells to chemotherapy and radiotherapy.It reglates the expression of many inflammatory genes and mediates the occurrence of inflammation.A large amount of evidence indicates that lunginflammation plays an important role in the development of lung cancer.In our study,we found that TGR5 inhibits lung inflammation by inhibiting the NF-?B signaling pathway.In mouse experiments,we found that the expression of inflammation genes such as IP-10,IL-1?,CCL4,CXCL2,IFN-y,and CCL3 in lung of TGR5 knockout mice was significantly higher than that of wild type mice.In lung adenocarcinoma cell line A549,we found that activation of TGR5 can effectively inhibit the expression of inflammatory cytokines induced by TNFasuch as COX-2,IP-10,CCL2,TNFa,and IL-8.In Luciferase experiments,we found that activation of TGR5 can effectively inhibit the transcriptional reglation of NF-?B to target genes.In Western-blot experiments,we found that phosphorylation of IKBa and nuclear translocation of p65 can be suppressed after TGR5 is activated.In summary,we can conclude that TGR5 can inhibit lung inflammation by inhibiting the NF-?B signaling pathway,and chronic inflammation is a common cause of cancer.Therefore,TGR5 may become an inhibitor of lung cancer.The PI3K/AKT pathway is abnormally expressed in many human cancers and is highly correlated with tumor growth,metastatic spread,and apoptosis resistance.Our study shows that TGR5 may inhibit the proliferation and migration of A549 cells and promote apoptosis by inhibiting the AKT signaling pathway.In MTT experiments,we found that activation of TGR5 can inhibit the proliferation of A549 cells.In the cell scratch experiment and RTCA experiment,we found that activation of TGR5 can inhibit the migration of A549 cells.Through double staining experiment,we found that activation of TGR5 can promote the apoptosis of A549 cells.Furthermore,we found that activation of TGR5 can inhibit the phosphorylation of AKT protein and the expression of Mcl-1,and Mcl-1 is a downstream target protein of AKT and has an anti-apoptotic function.We can speclate that TGR5 may inhibit the proliferation and migration of A549 cells and promote apoptosis by inhibiting the AKT signaling pathway.In summary,as a negative reglator of NF-?B signaling pathway and AKT signaling pathway,TGR5can effectively inhibit the progression of lung cancer and is a very promising target for the treatment of lung cancer.Therefore,the development of drugs that specifically activate lung TGR5 may be a new idea for the treatment of lung cancer.