Farnesoid X Receptor Deficiency in Mice Leads to Increased Intestinal Epithelial Cell Proliferation and Tumor Development

Abstract

Increased dietary fat consumption is associated with colon cancer development. The exact mechanism by which fat induces colon cancer is not clear, however, increased bile acid excretion in response to high-fat diet may promote colon carcinogenesis. The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily, and bile acids are endogenous ligands of FXR. FXR is highly expressed in the intestine and liver where FXR is essential for maintaining bile acid homeostasis. The role of FXR in intestine cancer development is not known. The current study evaluated the effects of FXR deficiency in mice on intestinal cell proliferation and cancer development. The results showed that FXR deficiency resulted in increased colon cell proliferation, which was accompanied by an up-

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

“…Studies have shown that mice deficient in FXR have increased colonic tumorigenesis and that the FXR antitumorigenic effects are at least partially due to BAindependent mechanisms, namely by regulating intestinal integrity and inflammation and protection from genotoxic compounds (13,21,25,44). FXR has also been suggested to suppress colon tumorigenesis by increasing apoptosis and suppressing epidermal growth factor receptor-mediated cell proliferation (21,25,30).…”

“…FXR is an adopted nuclear receptor responsible for regulating free BA levels in both liver and intestine and has been suggested to be a potential tumor suppressor for colon cancer development (7,21,25). Studies have shown that mice deficient in FXR have increased colonic tumorigenesis and that the FXR antitumorigenic effects are at least partially due to BAindependent mechanisms, namely by regulating intestinal integrity and inflammation and protection from genotoxic compounds (13,21,25,44).…”

“…5B). Silencing of FXR alone is not sufficient to initiate colon cancer development, but activation of remnant FXR in healthy tissues may play an important role in preventing and inhibiting the promotion of colon cancer (21,25,44). Restoration of basal FXR expression through inhibition of DNA methylation or KRAS signaling, or through activation of residual FXR, might slow or prevent the progression of colon cancer either through direct antiproliferative or chemopreventative mechanisms.…”

“…FXR critically regulates the homoeostasis of BAs, including BA synthesis, transport, and intestinal reabsorption, as well as the free intracellular concentration of BAs to prevent their accumulation to cytotoxic levels (9,12,26,39,47). FXR deficiency in mice promotes the development of intestinal tumors (21,25), implicating FXR as a tumor suppressor. Furthermore, overexpression of a constitutively active form of FXR decreases tumor size in mouse xenograft models (25).…”

Transcriptional Regulation of the Intestinal Nuclear Bile Acid Farnesoid X Receptor (FXR) by the caudal-related Homeobox 2 (CDX2)

“…The ability of FXR to reduce BA synthesis while inducing BA detoxification is of critical importance because high levels of circulating BA can increase hepatic and intestinal susceptibility to tumorigenesis (28 -31). Notably, the expression of FXR in the gut is restricted to the differentiated compartment of the intestinal epithelium (29,32), and its activation by BAs will result not only in BA detoxification but also in increased apoptosis and consequent removal of genetically modified cells (29,33). Indeed, the protective role of FXR against CRC susceptibility has been demonstrated by our group and others in Fxr knock-out mice, where the first hit for CRC development was made by inactivating Apc mutations (29,33).…”