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  • In this study we have investigated the expression of FXR


    In this study, we have investigated the expression of FXR and TGR5 in CCA tissues in two independent cohorts of patients and determined their association with tumor clinicopathological parameters. The expression of both BA receptors was also evaluated in CCA human cells and normal human cholangiocytes in culture. Furthermore, the effect of selective FXR and TGR5 activation was studied on CCA growth (both in vivo and in vitro) using OCA and INT-777, respectively.
    Materials and methods
    Discussion The key findings reported here are related to the role of BA receptors FXR and TGR5 in CCA progression. Our data indicate that: (i) the expression of FXR is downregulated in CCA tissue compared to surrounding normal human liver and correlates with the degree of tumor cell differentiation. In contrast, TGR5 expression is upregulated in CCA tissue (particularly in perihilar vs intrahepatic tumors) compared to surrounding normal human liver, and correlates with perineural invasion; (ii) in vitro, CCA human cells are characterized by FXR downregulation and TGR5 upregulation compared to NHC; (iii) FXR agonist OCA halts the orthotopic CCA tumor growth in immunodeficient mice. In vitro, OCA inhibits CCA cell proliferation and migration, as well as the mitochondrial energy metabolism; and (iv) although TGR5 agonist INT-777 did not modify the orthotopic CCA tumor growth in immunodeficient mice, it stimulated the proliferation, migration and mitochondrial energy metabolism of CCA cells in vitro. Our data are consistent with the notion that regulation of FXR and/or TGR5 activities in CCA tumor cells may have potential therapeutic value. BAs are important organic molecules synthesized from cholesterol in hepatocytes, and their canaliculus secretion confers the driving force for the generation of the bile flow. In the last years, increasing number of evidence is expanding the knowledge of the role of BAs in health and disease. It is now clear that BAs are not mere detergent molecules mediating fat digestion and intestinal pkm2 of hydrophobic compounds (like liposoluble vitamins) after food intake, but they are also important regulators of different pathophysiological processes in the liver and extrahepatic tissues, including cell proliferation, survival, secretion, differentiation, metabolism, regeneration, fibrosis and inflammation, among others. The identification of FXR and TGR5 BA receptors has opened new and promising fields of research in physiology, pathology and pharmacology. FXR and TGR5 are differentially activated by distinct BAs and their activation mediates specific and complex responses regulating multiple pathophysiological processes. Moreover, there are four FXR isoforms, whose differential activation depends on their expression pattern and the BA pool composition [43]. The development of novel BA derivatives able to selectively target FXR or TGR5 (i.e. OCA and INT-777, respectively) has allowed to evaluate their therapeutic value for the treatment of liver diseases, including cholestatic, metabolic and cancer conditions. CCAs can arise as a consequence of prolonged cholestasis and inflammation in the liver [44], [45]. Although, novel tests have shown that BAs cannot be considered direct genotoxic agents [46], they may function as co-carcinogens by stimulating, via BA receptors, the proliferation, survival and inflammatory response of biliary epithelial cells [46]. We have confirmed in a larger number of CCA patients of two independent cohorts (Copenhagen and San Sebastian) previously reported observations [47] indicating FXR expression is lower in the tumors compared to surrounding normal liver tissue. Interestingly, FXR expression levels directly correlate with the degree of tumor differentiation, as FXR expression is lower in poorly-differentiated CCA tumors compared to moderate/well differentiated tumors. Since tumor differentiation status has a prognostic value [48], the analysis of FXR expression may help to characterize CCA tumor features. On the other hand, TGR5 expression is enhanced in CCA tumors compared to surrounding normal liver tissue in both cohorts of patients. Differences among CCA subtypes were also found, as TGR5 expression was higher in perihilar than in intrahepatic CCAs. Importantly, TGR5 expression in CCA tumors correlated with perineural invasion, which has important implications regarding the evolution of this cancer. Additionally, a similar expression pattern for FXR and TGR5 was observed in human CCA cells compared to normal human cholangiocytes in vitro. Therefore, the clinicopathological correlations for FXR and TGR5 expression reported here may be helpful to better characterize human CCA tumors and may have potential prognostic value.