Frequent amplification of c-myc in ground squirrel liver tumors associated with past or ongoing infection with a hepadnavirus.

Abstract

Persistent infection with hepatitis B virus (HBV) is a major cause of hepatoceliular carcinoma (HCC) in humans. HCC has also been observed in animals chronically infected with two other hepadnaviruses: ground squirrel hepatitis virus (GSHV) and woodchuck hepatitis virus (WHV). A distinctive feature of WHV is the early onset of woodchuck tumors, which may be correlated with a direct role of the virus as an insertional mutagen of myc genes: c-myc, N-myc, and predominantly the woodchuck N-myc2 retroposon. In the present study, we searched for integrated GSHV DNA and genetic alterations ofmyc genes in ground squirrel HCCs. Viral integration into host DNA was detected in only 3/14 squirrel tumors and did not result in insertional activation of myc genes, despite the presence of a squirrel locus homologous to the woodchuck N-myc2 gene. This suggests that GSHV may differ from WHV in its reduced ability to induce mutagenic integration events. However, the high frequency of c-myc amplification (6/14) observed in ground squirrel HCCs indicates that myc genes might be preferential effectors in the tumorigenic processes associated with rodent hepadnaviruses, a feature not reported so far in HBV-induced carcinogenesis. Together with previous observations, our results suggest that hepadnaviruses, despite dose genetic and biological properties, may use different pathways in the genesis of liver cancer.

Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis

“…In the woodchuck HCC model, 17% of animals infected by WHV developed primary liver cancers, despite negativation of the assay for WHV surface antigen in the serum and the appearance of antibodies to surface and capsid viral antigens; furthermore, WHV DNA was detected in tumor tissue from these animals, with a much lower copy per cell number than in WHsAgpositive woodchucks (approximately 1 and 1000 molecules per cell, respectively) (Korba et al, 1989;Gerin et al, 1991), an observation fairly similar to that made in human HCCs. Ground squirrel may also prove to be an interesting model, as GSHV DNA sequences have been identified in HCCs developing in completely seronegative animals (Transy et al, 1992). Another piece of evidence for a direct role of HBV in liver cancer arises from the detection of HBV DNA in HCCs in HBsAg-negative patients, developing on non-cirrhotic tissue, histologically very similar to normal liver; thus, cirrhosis alone cannot account for the induction of cancer in these cases (Bre´chot, 1998).…”

c-Fos Is a Mediator of the c-Myc-induced Apoptotic Signaling in Serum-deprived Hepatoma Cells via the p38 Mitogen-activated Protein Kinase Pathway

“…c-Myc-dependent apoptosis has also been reported in target tissues of transgenic mice, such as pancreatic ␤ cells (19) and hepatocytes (20). On the contrary, over-expression of the c-myc gene is implicated in hepatocellular carcinoma in the hepadnavirus-infected woodchucks (21) and ground squirrels (22). Likewise, amplification of proto-oncogenes such as c-myc has been reported in a variety of tumors and is relatively common in carcinomas and sarcomas in humans (23)(24)(25).…”

Occult Lifelong Persistence of Infectious Hepadnavirus and Residual Liver Inflammation in Woodchucks Convalescent From Acute Viral Hepatitis

“…This assumption is based on a growing number of observations indicating that HBV infection can appear in recipients of organs from HBV serologically negative donors, [7][8][9][10][11][12] and that hepatocellular carcinoma (HCC) with integrated HBV genomic sequences can arise in HBVseronegative patients 13-15 and animals. 16,17 There is also the likelihood that some individuals who develop subclinical infection after exposure to HBV become serologically silent carriers of virus and a potential source of infection to nonimmune humans.The main aims of this present study were to determine overall longevity and the sites of hidden hepadnavirus replication that continues after recovery from an episode of self-limited acute hepatitis (SLAH), to assess infectivity and pathogenic competence of the carried virus, and to recognize the long-term pathological consequences of this silent form of hepadnavirus infection. To circumvent practical and ethical difficulties associated with long-term study of individuals considered to be completely healthy, in particular with obtaining multiple liver biopsy samples, we have followed, for up to 6 years, woodchucks inoculated with woodchuck hepatitis virus (WHV), which is the closest relative of HBV among hepadnaviruses.…”

“…This assumption is based on a growing number of observations indicating that HBV infection can appear in recipients of organs from HBV serologically negative donors, [7][8][9][10][11][12] and that hepatocellular carcinoma (HCC) with integrated HBV genomic sequences can arise in HBVseronegative patients [13][14][15] and animals. 16,17 There is also the likelihood that some individuals who develop subclinical infection after exposure to HBV become serologically silent carriers of virus and a potential source of infection to nonimmune humans.…”