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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.
Afiliación
  • Fu T; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
  • Coulter S; Storr Liver Centre, Westmead Institute for Medical Research and Sydney Medical School, University of Sydney, Westmead NSW 2145, Australia.
  • Yoshihara E; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
  • Oh TG; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
  • Fang S; Severance Biomedical Science Institute, BK21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, South Korea.
  • Cayabyab F; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
  • Zhu Q; Department of Medicine, University of California San Diego, La Jolla, CA 92037, USA.
  • Zhang T; Waitt Biophotonics Core, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
  • Leblanc M; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
  • Liu S; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
  • He M; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
  • Waizenegger W; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
  • Gasser E; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
  • Schnabl B; Department of Pediatrics, University of California San Diego, La Jolla, CA 92037, USA.
  • Atkins AR; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
  • Yu RT; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
  • Knight R; 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.
  • Liddle C; Storr Liver Centre, Westmead Institute for Medical Research and Sydney Medical School, University of Sydney, Westmead NSW 2145, Australia.
  • Downes M; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: downes@salk.edu.
  • Evans RM; 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.
Cell ; 176(5): 1098-1112.e18, 2019 02 21.
Article en En | MEDLINE | ID: mdl-30794774
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-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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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Células Madre Neoplásicas / Receptores Citoplasmáticos y Nucleares / Neoplasias Intestinales Tipo de estudio: Etiology_studies / Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: Cell Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Células Madre Neoplásicas / Receptores Citoplasmáticos y Nucleares / Neoplasias Intestinales Tipo de estudio: Etiology_studies / Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: Cell Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos