Premium
Modeling hepatitis B virus X–induced hepatocellular carcinoma in mice with the sleeping beauty transposon system
Author(s) -
Keng Vincent W.,
Tschida Barbara R.,
Bell Jason B.,
Largaespada David A.
Publication year - 2011
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.24091
Subject(s) - hbx , sleeping beauty transposon system , cancer research , biology , hepatitis b virus , carcinogenesis , transgene , rna interference , hepatocellular carcinoma , oncogene , virology , virus , mutant , cancer , gene , transposable element , genetics , cell cycle , rna
The mechanisms associated with hepatitis B virus (HBV)–induced hepatocellular carcinoma (HCC) remain elusive, and there are currently no well‐established animal models for studying this disease. Using the Sleeping Beauty transposon as a delivery system, we introduced an oncogenic component of HBV, the hepatitis B virus X ( HBx ) gene, into the livers of fumarylacetoacetate hydrolase ( Fah ) mutant mice via hydrodynamic tail vein injections. Coexpression of Fah complementary DNA from the transposon vector allowed for the selective repopulation of genetically corrected hepatocytes in Fah mutant mice. The process of hydrodynamic delivery induced liver inflammation, and the subsequent selective repopulation of hepatocytes carrying the transgene(s) could provide useful genetic information about the mechanisms of HBV‐induced hyperplasia. Short hairpin RNA directed against transformation‐related protein 53 ( shp53 ) or other tumor suppressor genes and oncogenes [e.g., constitutively active neuroblastoma RAS viral (v‐ras) oncogene homolog with Gly12Val substitution ( NRAS G12V )] could also be codelivered with HBx by this system so that we could determine whether oncogenic cooperation existed. We found that the expression of HBx induced the activation of β‐catenin expression in hydrodynamically injected livers, and this indicated its association with the Wnt signaling pathway in HBV‐induced hyperplasia. HBx coinjected with shp53 accelerated the formation of liver hyperplasia in these mice. As expected, constitutively active NRAS G12V alone was sufficient to induce liver hyperplasia, and its tumorigenicity was augmented when it was coinjected with shp53 . Interestingly, HBx did not seem to cooperate with constitutively active NRAS G12V in driving liver tumorigenesis. Conclusion: This system can be used as a model for studying the various genetic contributions of HBV to liver hyperplasia and finally HCC in an in vivo system. (H EPATOLOGY 2010;.)