1. FXR Regulates Intestinal Cancer Stem Cell Proliferation
- Author
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Eiji Yoshihara, Mathias Leblanc, Ting Fu, Sally Coulter, Tae Gyu Oh, Tong Zhang, Ronald M. Evans, Sihao Liu, Qiyun Zhu, Mingxiao He, Ruth T. Yu, Bernd Schnabl, Fritz Cayabyab, Emanuel Gasser, Christopher Liddle, Michael Downes, Rob Knight, Wanda Waizenegger, Annette R. Atkins, and Sungsoon Fang
- Subjects
Colorectal cancer ,Cytoplasmic and Nuclear ,Receptors, Cytoplasmic and Nuclear ,Inbred C57BL ,Medical and Health Sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Risk Factors ,Receptors ,Lgr5(+) intestinal stem cells ,genetic and dietary risk factors ,Wnt Signaling Pathway ,Cancer ,0303 health sciences ,Deoxycholic acid ,Wnt signaling pathway ,LGR5 ,Biological Sciences ,Colo-Rectal Cancer ,Gene Expression Regulation, Neoplastic ,Intestines ,Organoids ,Liver ,Neoplastic Stem Cells ,Stem Cell Research - Nonembryonic - Non-Human ,Stem cell ,Colorectal Neoplasms ,Deoxycholic Acid ,Signal Transduction ,Taurocholic Acid ,colon cancer progression ,BA-FXR axis ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,Cell Line ,Bile Acids and Salts ,03 medical and health sciences ,Cancer stem cell ,Intestinal Neoplasms ,medicine ,Animals ,Humans ,030304 developmental biology ,Nutrition ,Cell Proliferation ,Neoplastic ,Cell growth ,Prevention ,medicine.disease ,Stem Cell Research ,Mice, Inbred C57BL ,chemistry ,Gene Expression Regulation ,Cancer research ,Farnesoid X receptor ,Digestive Diseases ,030217 neurology & neurosurgery ,Developmental Biology - 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.
- Published
- 2018