Journal article
Chronic liver injury alters driver mutation profiles in hepatocellular carcinoma in mice
Hepatology (Baltimore, Md.), Vol.67(3), pp.924-939
03/2018
DOI: 10.1002/hep.29565
PMCID: PMC5826818
PMID: 28961327
Abstract
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.
A chronically damaged liver microenvironment influences the genetic mechanisms that drive hepatocarcinogenesis. (Hepatology 2018;67:924-939).
Details
- Title: Subtitle
- Chronic liver injury alters driver mutation profiles in hepatocellular carcinoma in mice
- Creators
- Jesse D Riordan - Department of Anatomy & Cell Biology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IACharlotte R Feddersen - Department of Anatomy & Cell Biology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IABarbara R Tschida - Masonic Cancer Center, Department of Pediatrics & Center for Genome Engineering, University of Minnesota, Minneapolis, MNPauline J Beckmann - Masonic Cancer Center, Department of Pediatrics & Center for Genome Engineering, University of Minnesota, Minneapolis, MNVincent W Keng - Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong KongMichael A Linden - Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MNKhalid Amin - Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MNChristopher S Stipp - Department of Biology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IADavid A Largaespada - Masonic Cancer Center, Department of Pediatrics & Center for Genome Engineering, University of Minnesota, Minneapolis, MNAdam J Dupuy - Department of Anatomy & Cell Biology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA
- Resource Type
- Journal article
- Publication Details
- Hepatology (Baltimore, Md.), Vol.67(3), pp.924-939
- Publisher
- United States
- DOI
- 10.1002/hep.29565
- PMID
- 28961327
- PMCID
- PMC5826818
- ISSN
- 1527-3350
- eISSN
- 1527-3350
- Grant note
- T32 GM067795 / NIGMS NIH HHS R01 CA132962 / NCI NIH HHS T32 GM007337 / NIGMS NIH HHS P30 CA086862 / NCI NIH HHS R01 CA113636 / NCI NIH HHS
- Language
- English
- Date published
- 03/2018
- Academic Unit
- Molecular Physiology and Biophysics; Anatomy and Cell Biology; Pathology; Biology
- Record Identifier
- 9983991990202771
Metrics
29 Record Views