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.
Highlights
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
Sodium salts of free bile acids-cholic acid (CA), deoxycholic acid (DCA), chenodeoxycholic acid (CDCA), and their glycine conjugates-glycocholic acid (GCA), glycochenodeoxycholic acid (GDCA) and glycochenodeoxycholic acid (GCDCA) were purchased from Sigma Corp (St Louis, MO)
The mRNA expression of FXR was detected as 1.16 folds (200 μM CA group), 1.12 folds (200 μM DCA group), 1.16 folds (200 μM CDCA group), 0.60 folds (800 μM GCA group), 0.61 folds (400 μM GDCA group) and 0.61 folds (400 μM GCDCA group), compared with the control group
Summary
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. There is an urgent need to develop effective new therapeutic strategies. It is known that the balance of various bile acids is crucial to lipid metabolism. In view of previous studies, bile acids are thought as the metabolic products of lipid metabolism, and as possible tumor regulating factors. 1) Do changes in the human bile acid composition affect the activation of nuclear receptors and cell signaling pathways in the cholangiocarcinoma in a physiologically significant way? 2) What is the underlying molecular mechanism of various types of bile acids on the occurrence and development of cholangiocarcinoma? There are a number of important questions yet to be answered. 1) Do changes in the human bile acid composition affect the activation of nuclear receptors and cell signaling pathways in the cholangiocarcinoma in a physiologically significant way? 2) What is the underlying molecular mechanism of various types of bile acids on the occurrence and development of cholangiocarcinoma?
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