Author information
1
Department of Anatomy & Cell Biology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, 52242, USA.
2
Masonic Cancer Center, Department of Pediatrics & Center for Genome Engineering, University of Minnesota, Minneapolis, MN, 55455, USA.
3
Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong.
4
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA.
5
Department of Biology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, 52242, USA.
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 novel 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.