Impact of bile acids on the growth of human cholangiocarcinoma via FXR

Abstract

BackgroundThe objective of the study was to investigate the effect of different types of bile acids on proliferation of cholangiocarcinoma and the potential molecular mechanisms.MethodsPCR 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.ResultsFree 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.ConclusionsThe 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.

Inhibition of leydig tumor growth by farnesoid X receptor activation: The in vitro and in vivo basis for a novel therapeutic strategy

“…Indeed, recent studies have highlighted an oncosuppressive role for FXR in a variety of cancer cell types. [8][9][10][11][12][13][14]17,36 However, direct evidence is missing for the in vivo effects of FXR activation in affecting Leydig carcinogenesis. In our study, we have provided the first evidence that GW4064, a synthetic ligand of FXR, induces Leydig tumor regression by a mechanism that involves both inhibition of cell proliferation and induction of apoptosis.…”

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

“…Bile acids are able to activate the EGFR via a transforming growth factor (TGF) α-dependent mechanism, thereby stimulating cholangiocyte proliferation 126 . Moreover, conjugated bile acids such as glycochenodeoxycholic acid downregulate the expression of the bile acid receptor farnesoid X-activated receptor (FXR, also known as bile acid receptor) and promote CCA growth in vivo; this event is inhibited by the administration of FXR agonists 127 . Moreover, growth-promoting effects of conjugated bile acids via the activation of sphingosine 1-phosphate receptor 2 have been reported 128,129 .…”

The roles of bile acids and sphingosine-1-phosphate signaling in the hepatobiliary diseases

“…The activation of EGFR by bile acids resulted in increased expression of cyclooxygenase-2 (COX-2). Moreover, conjugated bile acids have been shown to decrease FXR expression in vitro and to promote cholangiocellular carcinoma growth in vivo (47). However, the potential interaction between bile acids and sphingolipids has been overlooked until recently.…”