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FXR Regulates Intestinal Cancer Stem Cell Proliferation

Authors
 Ting Fu  ;  Sally Coulter  ;  Eiji Yoshihara  ;  Tae Gyu Oh  ;  Sungsoon Fang  ;  Fritz Cayabyab  ;  Qiyun Zhu  ;  Tong Zhang  ;  Mathias Leblanc  ;  Sihao Liu  ;  Mingxiao He  ;  Wanda Waizenegger  ;  Emanuel Gasser  ;  Bernd Schnabl  ;  Annette R. Atkins  ;  Ruth T. Yu  ;  Rob Knight  ;  Christopher Liddle  ;  Michael Downes  ;  Ronald M. Evans 
Citation
 CELL, Vol.176(5) : 1098-1112.e18, 2019 
Journal Title
 CELL 
ISSN
 0092-8674 
Issue Date
2019
Keywords
BA-FXR axis ; Lgr5(+) intestinal stem cells ; colon cancer progression ; genetic and dietary risk factors
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.
Full Text
https://www.sciencedirect.com/science/article/pii/S0092867419300996
DOI
10.1016/j.cell.2019.01.036
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Fang, Sungsoon(황성순) ORCID logo https://orcid.org/0000-0003-0201-5567
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/169893
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