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.

FXR silencing in human colon cancer by DNA methylation and KRAS signaling

“…Studies, on small samples sizes, have shown that FXR was silenced in later stages of colon cancer, implicating FXR as a marker of tumor malignancy (6,16). Although polymorphisms within the FXR gene have been associated with decreased function in intrahepatic cholestasis of pregnancy (ICP) (23), no clinically known mutations exist within the FXR gene to explain decreased FXR expression or function in human colon cancer.…”

The farnesoid X receptor and colon cancer

“…[24] FXR mRNA expression is reduced in colon adenomas and even more profoundly in colon adenocarcinomas. [32,33] Diminished FXR expression is associated with advanced CRC stage and an adverse prognosis. [26,33] Colon cancer risk increases substantially with chronic intestinal inflammation as in inflammatory bowel disease, including both Crohn's and ulcerative colitis (UC).…”

“…[32,33] Diminished FXR expression is associated with advanced CRC stage and an adverse prognosis. [26,33] Colon cancer risk increases substantially with chronic intestinal inflammation as in inflammatory bowel disease, including both Crohn's and ulcerative colitis (UC). [34,35] FXR activation decreases the production of pro-inflammatory cytokines, such as interleukin (IL) 1-beta, IL-2, IL-6, tumor necrosis factor-alpha and interferon-gamma, thereby reducing inflammation and intestinal permeability.…”

FXR and liver carcinogenesis

“…Compared with matched normal tissues, FXR expression is significantly reduced in human tumor specimens [21][22][23][24][25] , and the downregulation of FXR is associated with malignant clinicopathological characteristics [23,26] . Loss of FXR leads to early mortality and/or promotes intestinal carcinogenesis in the mice with either a mutated APC gene (APC min/+ ) or chronic colitis [26][27][28] . FXR deficiency also facilitates the progression of colorectal adenocarcinoma in C57BL/6 mice treated with the colon carcinogen azoxymethane [28] .…”