FXR Regulates Intestinal Cancer Stem Cell Proliferation.
Increased levels of intestinal bile acids (BAs) are a risk factor for colorectal cancer (CRC). Here, we show that the convergence of dietary factors (high-fat diet) and dysregulated WNT signaling (APC mutation) alters BA profiles to drive malignant transformations in Lgr5-expressing (Lgr5+
) cancer stem cells and promote an adenoma-to-adenocarcinoma progression. Mechanistically, we show that BAs that antagonize intestinal farnesoid X receptor (FXR) function, including tauro-β-muricholic acid (T-βMCA) and deoxycholic acid (DCA), induce proliferation and DNA damage in Lgr5+
cells. Conversely, selective activation of intestinal FXR can restrict abnormal Lgr5+
cell growth and curtail CRC progression. This unexpected role for FXR in coordinating intestinal self-renewal with BA levels implicates FXR as a potential therapeutic target for CRC.
Fu, T; Coulter, S; Yoshihara, E; Oh, TG; Fang, S; Cayabyab, F; Zhu, Q; Zhang, T; Leblanc, M; Liu, S; He, M; Waizenegger, W; Gasser, E; Schnabl, B; Atkins, AR; Yu, RT; Knight, R; Liddle, C; Downes, M; Evans, RM
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