Cocarcinogenic Effects of Intrahepatic Bile Acid Accumulation in Cholangiocarcinoma Development

Abstract

Bile acid accumulation in liver with cholangiolar neoplastic lesions may occur before cholestasis is clinically detected. Whether this favors intrahepatic cholangiocarcinoma development has been investigated in this study. The E. coli RecA gene promoter was cloned upstream from Luc2 to detect in vitro direct genotoxic ability by activation of SOS genes. This assay demonstrated that bile acids were not able to induce DNA damage. The genotoxic effect of the DNA-damaging agent cisplatin was neither enhanced nor hindered by the hepatotoxic and hepatoprotective glycochenodeoxycholic and glycoursodeoxycholic acids, respectively. In contrast, thioacetamide metabolites, but not thioacetamide itself, induced DNA damage. Thus, thioacetamide was used to induce liver cancer in rats, which resulted in visible tumors after 30 weeks. The effect of bile acid accumulation on initial carcinogenesis phase (8 weeks) was investigated in bile duct ligated (BDL) animals. Serum bile acid measurement and determination of liver-specific healthy and tumor markers revealed that early thioacetamide treatment induced hypercholanemia together with upregulation of the tumor marker Neu in bile ducts, which were enhanced by BDL. Bile acid accumulation was associated with increased expression of interleukin (IL)-6 and downregulation of farnesoid X receptor (FXR). Bile duct proliferation and apoptosis activation, with inverse pattern (BDL > thioacetamide þ BDL >> thioacetamide vs. thioacetamide > thioacetamide þ BDL > BDL), were observed. In conclusion, intrahepatic accumulation of bile acids does not induce carcinogenesis directly but facilitates a cocarcinogenic effect due to stimulation of bile duct proliferation, enhanced inflammation, and reduction in FXR-dependent chemoprotection.

Phosphorylation of Bcl-2 plays an important role in glycochenodeoxycholate-induced survival and chemoresistance in HCC

“…Bile salts and bile acids are considered to be potential carcinogens. For example, bile acids play a role in colorectal carcinogenesis through ERKs and PKC signaling pathway (41); intrahepatic bile acid accumulation may have cocarcinogenic effects on the development of cholangiocarcinoma (42). Glycochenodeoxycholate (Glycine conjugate of chenodexycholate) is the main ingredient in the bile.…”

Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

“…Moreover, growth-promoting effects of conjugated bile acids via the activation of sphingosine 1-phosphate receptor 2 have been reported 128,129 . In sum, in experimental models, bile acid accumulation during cholestatic conditions seems to facilitate carcinogenesis via the induction of biliary proliferation and inflammation rather than by direct mutagenic effects 36 .…”

“…All these risk factors share, as a putative pathogenic mech anism, chronic inflammation involving the biliary tract 34,35 . This process might be favoured by local intrahepatic accumulation of bile acids, even in the absence of net cholestasis 36 . Several toxic and environmental factors are known or suspected to be Nature Reviews | Gastroenterology & Hepatology 1,5,30 .…”

FXR and liver carcinogenesis

“…The physiological concentration or the modest elevation of BA levels, such as in exclusively FXR or SHP individual knockout mice, cannot lead to YAP activation [41] . Consistent with the observation that elevated BA levels in mice fed with a 0.2% cholic acid diet significantly promoted N-nitrosodiethylamine-initiated hepatocellular carcinoma (HCC) [19] formation, Lozano et al [45] revealed that intrahepatic BA accumulation in bile-duct-ligated rats facilitated the carcinogenic effects of thioacetamide metabolites in cholangiocarcinoma development. The persistently high levels of BA enhanced the inflammation and bile duct proliferation, and led to the downregulation of FXR expression.…”

“…The persistently high levels of BA enhanced the inflammation and bile duct proliferation, and led to the downregulation of FXR expression. Those data indicate that during hepatocarcinogenesis, BAs may function as tumor promoters as well as DNA-damaging initiators [19,45] . The imbalanced ratio of free and conjugated BAs also promotes the growth of human cholangiocarcinoma via FXR [46] .…”