title: 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 + BDL >> thioacetamide vs. thioacetamide > thioacetamide + 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.
  
  
  CONCLUSIONS
  This study reveals that bile acids foster cocarcinogenic events that impact cholangiocarcinoma.
authors.affiliation: Department of Physiology and Pharmacology, Campus Miguel de Unamuno E.D. 37007-Salamanca, Spain. jjgmarin@usal.es.
authors.forename: Elisa
authors.initials: E
authors.lastname: Lozano
authors.forename: Laura
authors.initials: L
authors.lastname: Sanchez-Vicente
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Monte
authors.forename: Elisa
authors.initials: E
authors.lastname: Herraez
authors.forename: Oscar
authors.initials: O
authors.lastname: Briz
authors.forename: Jesus M
authors.initials: JM
authors.lastname: Banales
authors.forename: Jose J G
authors.initials: JJ
authors.lastname: Marin
authors.forename: Rocio I R
authors.initials: RI
authors.lastname: Macias
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001647:Bile Acids and Salts / Q000097:blood / Q000378:metabolism*; D001650:Bile Duct Neoplasms / Q000473:pathology*; D001653:Bile Ducts, Intrahepatic / Q000473:pathology* / Q000601:surgery; D014408:Biomarkers, Tumor / Q000096:biosynthesis; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018281:Cholangiocarcinoma / Q000473:pathology*; D002779:Cholestasis / Q000175:diagnosis / Q000473:pathology; D002793:Cholic Acids / Q000097:blood; D002945:Cisplatin / Q000494:pharmacology; D003043:Cocarcinogenesis; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D005999:Glycochenodeoxycholic Acid / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology / Q000473:pathology; D007249:Inflammation; D015850:Interleukin-6 / Q000096:biosynthesis; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms; D008297:Male; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D011938:Rec A Recombinases / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis; D013014:SOS Response, Genetics / Q000235:genetics; D013853:Thioacetamide / Q000494:pharmacology; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D014408:Biomarkers, Tumor; D002793:Cholic Acids; D002945:Cisplatin; D003432:Cross-Linking Reagents; D005999:Glycochenodeoxycholic Acid; D015850:Interleukin-6; D011938:Rec A Recombinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D018160:Receptors, Cytoplasmic and Nuclear; D013853:Thioacetamide; D000099150:Receptor, Farnesoid X-Activated; C483804:Erbb2 protein, rat