FGF19 and Met co‐activation in murine liver induces HCC: Biological and clinical relevance

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer‐related deaths worldwide. While several tyrosine kinase inhibitors (TKIs) have been approved as first or second line therapy for HCC, the overall efficacy of these agents is limited. Thus, developing useful animal models may shed light on the biology of HCC tumor and provide a platform to evaluate the potential therapeutic agents. In the current study, we found about 37% HCC patients have c‐Met and FGF19 up‐regulation together in about 110 HCC patient samples from China. Concomitant expression of FGF19 and c‐Met worked synergistically to induce tumor after 13 weeks post co‐delivery of the sleeping beauty plasmids and transposase via hydrodynamic tail vein injection. H&E staining showed the tumor histology to be reminiscent of HCC. Immunochemistry staining showed that these tumors had upregulation of glycogen synthetase and cell cycle protein cyclin‐D1. Ki‐67 staining was also increased in the tumor nodule. pERK and pmTOR were also activated in the tumor areas by IHC staining. The HCC tissue was assessed by RNA‐seq and compared to normal FVB mice. Such analysis revealed alterations in about 15 KEGG pathways including MAPK, RAS, RAP1, PI3K/AKT and others. Thus, we have generated a highly relevant animal model of a subset of human HCC, which can be used to address molecular mechanisms and test targeted therapy.Support or Funding Information1R01DK62277, 1R01DK100287,1R01CA204586 and Endowed Chair for Experimental Pathology (S.P.M.).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.