Transgenic expression of entire hepatitis B virus in mice induces hepatocarcinogenesis independent of chronic liver injury.
Hepatocellular carcinoma (HCC), the third leading cause of cancer deaths worldwide, is most commonly caused by chronic hepatitis B virus (HBV) infection. However, whether HBV plays any direct role in carcinogenesis, other than indirectly causing chronic liver injury by inciting the host immune response, remains unclear. We have established two independent transgenic mouse lines expressing the complete genome of a mutant HBV ("preS2 mutant") that is found at much higher frequencies in people with HCC than those without. The transgenic mice show evidence of stress in the endoplasmic reticulum (ER) and overexpression of cyclin D1 in hepatocytes. These mice do not show any evidence of chronic liver injury, but by 2 years of age a majority of the male mice develop hepatocellular neoplasms, including HCC. Unexpectedly, we also found a significant increase in hepatocarcinogenesis independent of necroinflammation in a transgenic line expressing the entire wildtype HBV. As in the mutant HBV mice, HCC was found only in aged--2-year-old--mice of the wildtype HBV line. The karyotype in all the three transgenic lines appears normal and none of the integration sites of the HBV transgene in the mice is near an oncogene or tumor suppressor gene. The significant increase of HCC incidence in all the three transgenic lines--expressing either mutant or wildtype HBV--therefore argues strongly that in absence of chronic necroinflammation, HBV can contribute directly to the development of HCC.
Pathology Service, Veterans Administration Medical Center, San Francisco, California, United States of America.
Bing
B
Na
Zhiming
Z
Huang
Qian
Q
Wang
Zhongxia
Z
Qi
Yongjun
Y
Tian
Cheng-Chan
CC
Lu
Jingwei
J
Yu
Martha A
MA
Hanes
Sanjay
S
Kakar
Eric J
EJ
Huang
J-H James
JH
Ou
Limin
L
Liu
T S Benedict
TS
Yen
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology* / Q000821:virology*; D002908:Chronic Disease; D019938:Cyclin D1 / Q000378:metabolism; D006515:Hepatitis B virus / Q000235:genetics* / Q000502:physiology; D008099:Liver / Q000293:injuries* / Q000473:pathology / Q000821:virology*; D008114:Liver Neoplasms, Experimental / Q000473:pathology* / Q000821:virology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional / Q000235:genetics; D009154:Mutation / Q000235:genetics; D056811:Unfolded Protein Response; D014779:Virus Replication / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism
D051176:beta Catenin; D019938:Cyclin D1