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FXR Regulates Intestinal Cancer Stem Cell Proliferation.

Fu, Ting; Coulter, Sally; Yoshihara, Eiji; Oh, Tae Gyu; Fang, Sungsoon; Cayabyab, Fritz; Zhu, Qiyun; Zhang, Tong; Leblanc, Mathias; Liu, Sihao; He, Mingxiao; Waizenegger, Wanda; Gasser, Emanuel; Schnabl, Bernd; Atkins, Annette R; Yu, Ruth T; Knight, Rob; Liddle, Christopher; Downes, Michael; Evans, Ronald M.
Cell; 176(5): 1098-1112.e18, 2019 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-30794774
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-ß-muricholic acid (T-ßMCA) 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.
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