| Literature DB >> 30794774 |
Ting Fu1, Sally Coulter2, Eiji Yoshihara1, Tae Gyu Oh1, Sungsoon Fang3, Fritz Cayabyab1, Qiyun Zhu4, Tong Zhang5, Mathias Leblanc1, Sihao Liu1, Mingxiao He1, Wanda Waizenegger1, Emanuel Gasser1, Bernd Schnabl6, Annette R Atkins1, Ruth T Yu1, Rob Knight7, Christopher Liddle2, Michael Downes8, Ronald M Evans9.
Abstract
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.Entities:
Keywords: BA-FXR axis; Lgr5(+) intestinal stem cells; colon cancer progression; genetic and dietary risk factors
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Year: 2019 PMID： 30794774 PMCID： PMC6701863 DOI： 10.1016/j.cell.2019.01.036
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582