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FXR EXPRESSION AND REGULATION IN of pro-inflammatory cytokines, such as interleukin
NORMAL INTESTINAL MUCOSA (IL) 1-beta, IL-2, IL-6, tumor necrosis factor-alpha and
interferon-gamma, thereby reducing inflammation and
[37]
[36]
FXR is expressed primarily in the GI tract, liver and intestinal permeability. Torres et al. showed that
kidney. [22,23] Modica et al. showed that murine FXR FXR expression was inversely correlated with neoplastic
[24]
(Nr1h4) is expressed at high levels in the small intestine progression and the severity of colonic inflammation in
and colon, whereas human FXR (NR1H4) is expressed at UC. FXR expression is also reduced in colonic mucosa
moderate levels in the colon. FXR expression is localized from patients with primary sclerosing cholangitis (PSC)
primarily to fully differentiated cells lining the intestinal and UC-associated neoplasia. Compared to patients with
epithelium of the ileum and colon. In the Apc min/+ UC alone, those with PSC-UC have diminished FXR
[24]
murine model of CRC, FXR messenger RNA (mRNA) expression in the right colon suggesting they are at a higher
levels were down-regulated in tumor tissue compared with risk of proximal colon neoplasia. [37]
adjacent normal mucosa. Likewise, in patients with familial
adenomatous polyposis (FAP) syndrome, FXR mRNA FXR AND COLON CARCINOGENESIS
expression was decreased in normal and neoplastic tissues.
In a human CRC cell line, HT-29 cells, restoring wild-type Although the above observations strongly implicate FXR
APC protein induced FXR expression, suggesting that as a tumor suppressor, the underlying mechanism
APC may directly or indirectly regulate FXR expression. is incompletely understood. No mutations have been
[24]
FXR can also be regulated at the transcriptional level by identified in the FXR gene in CRC. Several studies
[26]
the caudal-related homeobox 2. Moreover, Bailey et suggest the role of FXR in colon carcinogenesis is
[25]
[29]
al. showed that DNA methylation and KRAS signaling multifactorial. Modica et al. showed the importance
[26]
silence FXR in human CRC. In approximately, 12% of of Wnt signaling and apoptosis downstream of FXR.
human colon cancers and in several colon cancer cell lines, FXR promotes Wnt signaling with the expansion of basal
including SW620, FXR promoter methylation of a CpG proliferative intestinal cells, and a concomitant reduction
island results in very low FXR expression. Cabrerizo et in the apoptosis-competent apical epithelium. When FXR
[26]
al. found FXR promoter methylation at two additional is activated in CRC cells, induction of apoptosis results
[27]
CpG islands (-358 and -1890 bp). Furthermore, functional in the removal of genetically altered tumor cells. The
analysis of the 5’-promoter region of the human FXR gene same investigators showed that FXR activation increased
in HepG2 cells suggests that hepatic nuclear factor 1a may expression of several pro-apoptotic genes, including FAS,
be a transcription factor for FXR. [28] BAK1, P21, KLF4, FADD, CAS9 and P27. Maran et al.
[30]
showed that FXR deficiency increases intestinal cell
FXR IS AN INTESTINAL TUMOR SUPPRESSOR proliferation, accompanied by up-regulation of cyclin
D1 and IL-6. In addition, it was shown that sodium
In addition to its essential role in regulating lipid metabolism, taurocholate inhibits intestinal tumorigenesis by activating
emerging evidence supports a key role for FXR as an FXR, leading to increased Shp expression and consequent
intestinal tumor suppressor. In two mouse models of CRC, down-regulation of cyclin D1. [31]
Apc min/+ and chronic colitis, Modica et al. showed that
[29]
FXR deficiency increased adenoma size and number. In Several other potential mechanisms may account for FXR
[38]
a xenograft model, they showed that FXR reactivation via inhibition of intestinal tumor genesis. Peng et al. showed
adenoviral infection blocked tumor growth. Using Apc min/+ that Src-mediated cross-talk between FXR and the EGFR
and azoxymethane-induced mouse models of CRC, Maran inhibited human intestinal cell proliferation in vitro and
et al. confirmed that FXR was an intestinal tumor growth of human colon cancer xenografts in nude mice.
[30]
[39]
suppressor. Smith et al. showed that activating FXR Yang et al. has showed that FXR is a transcription factor
[31]
with sodium taurocholate markedly reduced adenoma for microRNA-22, and also a tumor suppressor which
formation in Apc min/+ mice. silences cyclin A gene expression in colon cancer cells. In
inflammation-associated intestinal neoplasia, activation of
FXR is down-regulated drastically in colon tumors from FXR is repressed by pro-inflammatory cytokines that activate
[40]
both murine (Apc min/+ ) and human FAP models of CRC. intestinal nuclear factor-kB signaling; the investigators
[24]
FXR mRNA expression is reduced in colon adenomas concluded that FXR not only inhibits inflammation, but also is
and even more profoundly in colon adenocarcinomas. [32,33] targeted by the inflammatory response, resulting in a vicious
Diminished FXR expression is associated with advanced cycle where reduced FXR activity causes less repression of
CRC stage and an adverse prognosis. [26,33] inflammation. Zhou et al. also showed that activation of
[41]
the PPARα-UGT axis repressed intestinal FXR-FGF15/19
Colon cancer risk increases substantially with chronic feed-back and exacerbates experimental colitis, thereby
intestinal inflammation as in inflammatory bowel possibly promoting intestinal tumorigenesis. In mice, both
disease, including both Crohn’s and ulcerative colitis PPARα knockout and treatment with recombinant FGF19
(UC). [34,35] FXR activation decreases the production strongly attenuated dextran sulfate sodium-induced colitis. [41]

Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ Issue 1 ¦ January 15, 2016 ¦ 25