In the a first in vitro indication of modulation of
In the 2003, a first in vitro indication of modulation of FXR expression in CRC showed that FXR expression was absent in undifferentiated colon carcinoma cell line SW480, while it was progressively increasing along with the degree of cell differentiation in Caco2 and HT29 cells, and its transcriptional ability could be activated by treating chronic health condition with its synthetic ligand GW4064 (de et al., 2004). Later, it was demonstrated that intestinal FXR expression is not ubiquitous but is limited to the differentiated compartment of the intestinal epithelial mucosa, and in particular is restricted to the fully differentiated cells lining the intestinal epithelium of the ileum and colon (Modica et al., 2008, Modica et al., 2010). Moreover, analysis of human and murine intestinal tumor and adjacent normal mucosa has revealed that FXR expression is strongly decreased during the transition from normal to neoplastically transformed epithelium (Modica et al., 2010). Intriguingly, FXR expression is inversely correlated with the degree of malignancy and poor clinical outcome (Lax et al., 2012, Bailey et al., 2014). It has also been shown that patients presenting with PSC associated to UC have a reduced FXR expression in the proximal colon compared to UC patients per se (Torres et al., 2013), possibly indicating that a reduced intestinal FXR activity contributes to concomitant UC and higher risk of proximal neoplasia in PSC patients. The relevance of FXR in CRC aroused also from mouse models with genetic modulation of FXR. The generation of FXR−/- murine models (Kok et al., 2003, Sinal et al., 2000) represents a milestone in the understanding of FXR molecular activity and have been a great tool for a great number of subsequent studies that provided tremendous insights in his involvement in the pathophysiology of disease of the gut-liver axis. Loss of FXR expression and function in mice increases susceptibility to chemically-induced colorectal carcinogenesis associated to inflammation (Maran et al., 2009), while transgenic FXR overexpression in gut cells reduces tumor growth and development (Modica et al., 2008). Moreover, any interference with normal intestinal FXR expression and activity associated with compromised BA homeostasis leads to increased production of cytotoxic, pro-inflammatory and pro-tumoral secondary BAs, such as DCA, both in human and rodents (Bayerdorffer et al., 1993, Flynn et al., 2007, Imray et al., 1992, Rainey et al., 1984, Reddy et al., 1977a). As previously mentioned, somatic APC mutation presents triggers colorectal carcinogenesis (Powell et al., 1992), and a germline mutation of APC affects patients with autosomal dominantly inherited FAP (Kinzler et al., 1991). Modica et al. have shown that FXR expression is greatly reduced in FAP patient and in Apc ± mice (Modica et al., 2008). Also, FXR deficiency results in increased adenoma size and number when crossed with an APCMin+/– mice, and is associated with a higher prevalence of tumors in azoxymethane-induced tumorigenesis (Modica et al., 2008, Maran et al., 2009). Of note, constitutive activation of FXR in colon cancer cells is able to suppress colonic epithelium proliferation and induce a pro-apoptotic genes network, while repressing antiapoptotic genes (Modica et al., 2008). The combinatorial loss of Apc and FXR suggested the presence of an Apc downstream effector able to modulate intestinal FXR expression. In fact, subsequent in vitro work and analysis of FAP patients samples, Apc ± and Cdx2−/− mouse models have demonstrated that CDX2 is the trigger of FXR expression in the intestine (Modica et al., 2014) (Fig. 1). Moreover, it has been recently shown that the link between Apc inactivation and loss of FXR expression is likely due to increased CpG methylation in the Fxr gene (Fig. 1) that in turn also compromises the transactivation of downstream FXR targets, such as the intestinal SHP and IBABP and goes along with accumulation of the proinflammatory gene Cox-2 (Selmin et al., 2016). Functional methylation of FXR promoter has also been shown in different CRC cell lines and in colonic tumor clinical samples (Bailey et al., 2014). Overall, gain and loss of FXR function models have shown a direct protective role of this BA-dependent transcription factor in CRC.