Expression of the nuclear bile acid receptor/farnesoid X receptor is reduced in human colon carcinoma compared to nonneoplastic mucosa independent from site and may be associated with adverse prognosis

Abstract

The nuclear bile acid receptor/farnesoid X receptor (FXR; NR1H4) is involved in bile acid homeostasis, cell proliferation and apoptosis and has been linked to intestinal carcinogenesis in mice. Aim of this study was to analyze FXR expression in human normal intestinal mucosa and colon carcinoma. We achieved systematic mapping of FXR expression of human intestinal mucosa and analysis of 75 human colon carcinomas using FXR immunohistochemistry on formalin-fixed, paraffin-embedded tissue. FXR expression gradually decreased from terminal ileum to the sigmoid colon with strongest expression in the terminal ileum (p < 0.001). FXR expression in carcinomas was reduced compared to peritumoral nonneoplastic mucosa (p < 0.000). Loss of FXR expression was significantly correlated with grading in tumors of the right colon (p = 0.008). FXR expression in tumor and normal tissue showed an inverse correlation with stage. FXR expression in tumor was inversely correlated with clinical outcome. No association was found with patients' age and sex. In nonneoplastic mucosa FXR expression concurred with low expression of Ki-67. In carcinomas, no association was found between FXR expression and Ki-67 and cyclin D1, respectively. Development of colon carcinoma in humans is associated with reduced FXR expression independent of site and may reflect an impaired defense against potentially carcinogenic bile acids along their intestinal gradient. In contrast to normal colon mucosa, FXR expression in carcinomas is not associated with low proliferation. Colon carcinomas with FXR expression seem to be associated with lower stage and a more favourable outcome compared to FXR negative carcinomas.