The Molecular Mechanism Of Bile Acid Promoting Growth And Invasion Of Cholangiocarcinoma Through Advanced Glycation End Product Receptor (RAGE)

PART1Expression of RAGE in Cholangiocarcinoma and Its Clinical Significance Background and Aim:Cholangiocarcinoma(CCA)is notoriously difficult to diagnose and is associated with high mortality.The receptor for advanced glycation end products(RAGE)is an oncogenic trans-membranous receptor and member of the immunoglobulin superfamily,enhanced expression of RAGE has been demonstrated in distinct tumors and several studies support its crucial role in tumor progression and metastasis by still unknown mechanisms.In this study,we investigated the expression and molecular mechanisms of RAGE in cholangiocarcinoam cells.Methods:RAGE protein expression in 51 cholangiocarcinoma tissue specimens was analyzed by immunohistochemistry,and its association with clinicopathologic factors and prognosis was also analyzed.Results:41 patients(80.4%%)were positive for RAGE?4 and 24 patients(47.1%)for RAGE?8.RAGE were associated with tumor extent.RAGE?8(HR 2.199;95%CI 1.072-4.511;p=0.032)were independent predictor of survival.In subgroup analysis,RAGE>8(HR 5.716;95%CI 1.456-22.448;p=0.012)and RAGE?8(HR 1.040;95%CI 1.003-1.079;p=0.036)were associated with shorter survival among patients with TNM 3-4 and larger tumor size respectly.Conclusions:The expression of RAGE is closely related to the prognosis of patients with cholangiocarcinoma.PART 2conjugated bile acids can mediated CCA progression through RAGEBackground and Aim:Cholangiocarcinoma(CCA)is a cancer originating from the epithelial lining of the biliary tree which makes up 10-25%of all primary liver cancers.Recent study show that alterations in bile acid metabolism have also been reported to increase the risk of CCA.CCA patients are often asymptomatic in an early stage,but often become symptomatic later because of obstructive jaundice.The imbalance of ratio of free and conjugated bile acids may play an important role in tumorigenesis of cholangiocarcinoma.So,it is very important to verify conjugated bile acids in the progression of CCA.Methods:Determined the levels of TCA or DCA in bile of cholangiocarcinoma(n=30)and cholangiolithiasis patients(n=20).And detect the interaction of bile acid and RAGE in the process of cholangiocarcinoma.Results:We also showed that RAGE,can be activated by taurocholate(TCA).TCA activited p-ERK was significantly inhibited by FFP-ZM1,a RAGE antagonist.We further show that taurocholic acid(TCA)activate the ERK1/2-signaling pathways and significantly stimulate CCA cell growth and invasion through RAGE in vitro.Conclusions:TCA can promote the progression of CCA through RAGE.