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Chronic liver injury alters driver mutation profiles in hepatocellular carcinoma in mice.
Riordan, Jesse D; Feddersen, Charlotte R; Tschida, Barbara R; Beckmann, Pauline J; Keng, Vincent W; Linden, Michael A; Amin, Khalid; Stipp, Christopher S; Largaespada, David A; Dupuy, Adam J.
Afiliación
  • Riordan JD; Department of Anatomy & Cell Biology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA.
  • Feddersen CR; Department of Anatomy & Cell Biology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA.
  • Tschida BR; Masonic Cancer Center, Department of Pediatrics & Center for Genome Engineering, University of Minnesota, Minneapolis, MN.
  • Beckmann PJ; Masonic Cancer Center, Department of Pediatrics & Center for Genome Engineering, University of Minnesota, Minneapolis, MN.
  • Keng VW; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong.
  • Linden MA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN.
  • Amin K; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN.
  • Stipp CS; Department of Biology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA.
  • Largaespada DA; Masonic Cancer Center, Department of Pediatrics & Center for Genome Engineering, University of Minnesota, Minneapolis, MN.
  • Dupuy AJ; Department of Anatomy & Cell Biology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA.
Hepatology ; 67(3): 924-939, 2018 03.
Article en En | MEDLINE | ID: mdl-28961327
Most hepatocellular carcinomas (HCCs) develop in a chronically injured liver, yet the extent to which this microenvironment promotes neoplastic transformation or influences selective pressures for genetic drivers of HCC remains unclear. We sought to determine the impact of hepatic injury in an established mouse model of HCC induced by Sleeping Beauty transposon mutagenesis. Chemically induced chronic liver injury dramatically increased tumor penetrance and significantly altered driver mutation profiles, likely reflecting distinct selective pressures. In addition to established human HCC genes and pathways, we identified several injury-associated candidates that represent promising loci for further study. Among them, we found that FIGN is overexpressed in human HCC and promotes hepatocyte invasion. We also validated Gli2's oncogenic potential in vivo, providing direct evidence that Hedgehog signaling can drive liver tumorigenesis in the context of chronic injury. Finally, we show that a subset of injury-associated candidate genes identifies two distinct classes of human HCCs. Further analysis of these two subclasses revealed significant trends among common molecular classification schemes of HCC. The genes and mechanisms identified here provide functional insights into the origin of HCC in a chronic liver damage environment. CONCLUSION: A chronically damaged liver microenvironment influences the genetic mechanisms that drive hepatocarcinogenesis. (Hepatology 2018;67:924-939).
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma Hepatocelular / Enfermedad Hepática Crónica Inducida por Sustancias y Drogas / Carcinogénesis / Neoplasias Hepáticas Límite: Animals / Humans / Male Idioma: En Revista: Hepatology Año: 2018 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma Hepatocelular / Enfermedad Hepática Crónica Inducida por Sustancias y Drogas / Carcinogénesis / Neoplasias Hepáticas Límite: Animals / Humans / Male Idioma: En Revista: Hepatology Año: 2018 Tipo del documento: Article Pais de publicación: Estados Unidos