Hepatitis C virus acts as a tumor accelerator by blocking apoptosis in a mouse model of hepatocarcinogenesis.
We developed hepatitis C virus (HCV) core-E1-E2 and HCV core transgenic mice on a common genetic background to assess the contribution of HCV structural proteins to hepatocarcinogenesis. Eight-week-old core-E1-E2, core, and nontransgenic mice inbred on the FVBxC57Bl/6 background were treated with diethylnitrosamine (DEN) and sacrificed at 32 weeks old. Proliferation and apoptosis were assessed by immunohistochemistry. The effect of viral proteins on apoptosis was evaluated in HepG2 cells in which apoptosis was induced by anti-Fas antibody. HCCs were identified at 32 weeks in the majority of DEN-treated mice from all three groups. The mean size of HCCs was significantly larger in core-E1-E2 transgenic (4.63 +/- 1.48 mm), compared with core transgenic (0.78 +/- 0.26 mm, P = .01), and nontransgenic (1.0 +/- 0.19 mm, P = .002) mice. While there were no differences in proliferation, the apoptotic index in core-E1-E2 transgenic HCCs was significantly lower than those found in core and non-transgenic HCCs. Core-E1-E2 transfected HepG2 cells demonstrated a significantly lower apoptotic index (0.35 +/- 0.11) compared with that of core transfected cells (0.74 +/- 0.07, P = .0103). Analysis of a Fas-induced apoptosis model in HCV transgenic mice confirmed that core-E1-E2 transgenic liver underwent significantly less apoptosis than transgenic tissue expressing core only. In conclusion, HCV core-E1-E2 transgenic mice develop significantly larger tumors than transgenic mice expressing core alone or nontransgenic mice. The accelerated tumor phenotype is attributable to suppression of apoptosis rather than enhanced proliferation. These data implicate HCV E1 and/or E2 in conjunction with core as antiapoptotic, tumor accelerator proteins.
Kamegaya
Yoshitaka
Y
Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Hiasa
Yoichi
Y
Zukerberg
Lawrence
L
Fowler
Nina
N
Blackard
Jason T
JT
Lin
Wenyu
W
Choe
Won H
WH
Schmidt
Emmett V
EV
Chung
Raymond T
RT
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D004052:Diethylnitrosamine; D004195:Disease Models, Animal; D016174:Hepacivirus / Q000472:pathogenicity*; D008114:Liver Neoplasms, Experimental / Q000209:etiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D014759:Viral Envelope Proteins / Q000502:physiology*; D019014:fas Receptor / Q000502:physiology
C087035:E1 protein, Hepatitis C virus; D014759:Viral Envelope Proteins; D019014:fas Receptor; C091015:glycoprotein E2, Hepatitis C virus; D004052:Diethylnitrosamine