Pleiotropic roles of FXR in liver and colorectal cancers

Abstract

Nuclear receptor farnesoid X receptor (FXR) is generally considered a cell protector of enterohepatic tissues and a suppressor of liver cancer and colorectal carcinoma (CRC). Loss or reduction of FXR expression occurs during carcinogenesis, and the FXR level is inversely associated with the aggressive behaviors of the malignancy. Global deletion of FXR and tissue-specific deletion of FXR display distinct effects on tumorigenesis. Epigenetic silencing and inflammatory context are two main contributors to impaired FXR expression and activity. FXR exerts its antitumorigenic function via the following mechanisms: 1) FXR regulates multiple metabolic processes, notably bile acid homeostasis; 2) FXR antagonizes hepatic and enteric inflammation; 3) FXR impedes aberrant activation of some cancer-related pathways; and 4) FXR downregulates a number of oncogenes while upregulating some tumor suppressor genes. Restoring FXR functions via its agonists provides a therapeutic approach for patients with liver cancer and CRC. However, an in-depth understanding of the species-specific pharmacological effects is a prerequisite for assessing the clinical safety and efficacy of FXR agonists in human cancer treatment.

Keywords: Bile acid; Colorectal cancer; FXR; Liver cancer.