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The Polyploid State Plays a Tumor-Suppressive Role in the Liver.
Zhang, Shuyuan; Zhou, Kejin; Luo, Xin; Li, Lin; Tu, Ho-Chou; Sehgal, Alfica; Nguyen, Liem H; Zhang, Yu; Gopal, Purva; Tarlow, Branden D; Siegwart, Daniel J; Zhu, Hao.
Afiliación
  • Zhang S; Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Zhou K; Simmons Comprehensive Cancer Center, Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Luo X; Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Li L; Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Tu HC; Alnylam Pharmaceuticals, Cambridge, MA 02142, USA.
  • Sehgal A; Alnylam Pharmaceuticals, Cambridge, MA 02142, USA.
  • Nguyen LH; Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Zhang Y; Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Gopal P; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Tarlow BD; Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Siegwart DJ; Simmons Comprehensive Cancer Center, Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Zhu H; Children's Research Institute, Departments of Pediatrics and Internal Medicine, Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: hao.zhu@utsouthwestern.edu.
Dev Cell ; 44(4): 447-459.e5, 2018 02 26.
Article en En | MEDLINE | ID: mdl-29429824
Most cells in the liver are polyploid, but the functional role of polyploidy is unknown. Polyploidization occurs through cytokinesis failure and endoreduplication around the time of weaning. To interrogate polyploidy while avoiding irreversible manipulations of essential cell-cycle genes, we developed orthogonal mouse models to transiently and potently alter liver ploidy. Premature weaning, as well as knockdown of E2f8 or Anln, allowed us to toggle between diploid and polyploid states. While there was no detectable impact of ploidy alterations on liver function, metabolism, or regeneration, mice with more polyploid hepatocytes suppressed tumorigenesis and mice with more diploid hepatocytes accelerated tumorigenesis in mutagen- and high-fat-induced models. Mechanistically, the diploid state was more susceptible to Cas9-mediated tumor-suppressor loss but was similarly susceptible to MYC oncogene activation, indicating that polyploidy differentially protected the liver from distinct genomic aberrations. This suggests that polyploidy evolved in part to prevent malignant outcomes of liver injury.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Poliploidía / Proteínas Represoras / Transformación Celular Neoplásica / Hígado / Neoplasias Hepáticas Experimentales / Regeneración Hepática / Proteínas de Microfilamentos Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Dev Cell Asunto de la revista: EMBRIOLOGIA Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Poliploidía / Proteínas Represoras / Transformación Celular Neoplásica / Hígado / Neoplasias Hepáticas Experimentales / Regeneración Hepática / Proteínas de Microfilamentos Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Dev Cell Asunto de la revista: EMBRIOLOGIA Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos