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Cell. 2019 Feb 21;176(5):1098-1112.e18. doi: 10.1016/j.cell.2019.01.036.

FXR Regulates Intestinal Cancer Stem Cell Proliferation.

Author information

1
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
2
Storr Liver Centre, Westmead Institute for Medical Research and Sydney Medical School, University of Sydney, Westmead NSW 2145, Australia.
3
Severance Biomedical Science Institute, BK21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, South Korea.
4
Department of Medicine, University of California San Diego, La Jolla, CA 92037, USA.
5
Waitt Biophotonics Core, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
6
Department of Pediatrics, University of California San Diego, La Jolla, CA 92037, USA.
7
Department of Medicine, University of California San Diego, La Jolla, CA 92037, USA; Department of Computer Science and Engineering, University of California San Diego, La Jolla, CA 92037, USA.
8
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: downes@salk.edu.
9
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: evans@salk.edu.

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.

KEYWORDS:

BA-FXR axis; Lgr5(+) intestinal stem cells; colon cancer progression; genetic and dietary risk factors

PMID:
30794774
DOI:
10.1016/j.cell.2019.01.036

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