title: Impact of bile acids on the growth of human cholangiocarcinoma via FXR.
abstract: BACKGROUND
  The objective of the study was to investigate the effect of different types of bile acids on proliferation of cholangiocarcinoma and the potential molecular mechanisms.
  
  
  METHODS
  PCR assay and Western blot were performed to detect the expression of farnesoid × receptor (FXR) in mRNA and protein level. Immunohistochemical analysis was carried out to monitor the expression of FXR in cholangiocarcinoma tissues from 26 patients and 10 normal controls. The effects on in vivo tumor growth were also studied in nude mouse model.
  
  
  RESULTS
  Free bile acids induced an increased expression of FXR; on the contrary, the conjugated bile acids decreased the expression of FXR. The FXR effect has been illustrated with the use of the FXR agonist GW4064 and the FXR antagonist GS. More specifically, when the use of free bile acids combined with FXR agonist GW4064, the tumor cell inhibitory effect was even more pronounced. But adding FXR antagonist GS into the treatment attenuated the tumor inhibitory effect caused by free bile acids. Combined treatment of GS and CDCA could reverse the regulating effect of CDCA on the expression of FXR. Administration of CDCA and GW 4064 resulted in a significant inhibition of tumor growth. The inhibitory effect in combination group (CDCA plus GW 4064) was even more pronounced. Again, the conjugated bile acid-GDCA promoted the growth of tumor. We also found that FXR agonist GW4064 effectively blocked the stimulatory effect of GDCA on tumor growth. And the characteristic and difference of FXR expressions were in agreement with previous experimental results in mouse cholangiocarcinoma tissues. There was also significant difference in FXR expression between normal and tumor tissues from patients with cholangiocarcinoma.
  
  
  CONCLUSIONS
  The imbalance of ratio of free and conjugated bile acids may play an important role in tumorigenesis of cholangiocarcinoma. FXR, a member of the nuclear receptor superfamily, may mediate the effects induced by the bile acids.
authors: Division of General Surgery, Shanghai Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
authors: Jiaqi
authors: J
authors: Dai
authors: Hongxia
authors: H
authors: Wang
authors: Yihui
authors: Y
authors: Shi
authors: Ying
authors: Y
authors: Dong
authors: Yinxin
authors: Y
authors: Zhang
authors: Jian
authors: J
authors: Wang
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology*; D002460:Cell Line; D018281:Cholangiocarcinoma / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D007555:Isoxazoles; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C412815:GW 4064