The hepatitis B virus X gene potentiates c-myc-induced liver oncogenesis in transgenic mice

Abstract

The hepatitis B virus X protein (HBx) is thought to be implicated in the development of hepatocellular carcinoma, but its exact function remains controversial. Transgenic mice from PEX7 and AX16 lineages that express HBx in the liver under control of di erent viral regulatory elements develop no liver pathology (Billet et al., 1995). We have crossed these two mouse lineages with WHV/c-myc oncomice in which liver-speci®c expression of c-myc driven by woodchuck hepatitis virus (WHV) regulatory sequences causes liver cancer in all animals. The average tumor latency was shortened by 2 to 3 months in bitransgenic animals from all populations compared with simple c-myc transgenic littermates. At preneoplastic stages, adult bitransgenic mice showed four to ®vefold enhanced expression of the c-myc transgene, increased hepatocyte proliferation and more extensive liver lesions compared with simple WHV/c-myc transgenics. Thus in this model, HBx alone has no direct pathological e ect but it is shown to accelerate tumor development induced by c-myc. The data presented here ®rmly establish the oncogenic potential of HBx, apparently acting as a tumor promoter. This model o ers unique opportunities to investigate the mechanisms by which HBx trans-activates the expression of target genes and deregulates the hepatocyte growth control in vivo.

p53-independent apoptotic effects of the hepatitis B virus HBx protein in vivo and in vitro

“…HBx transgenic mice from AX16 and PEX7 lines produce weak amounts of the HBx protein in the neonatal liver (Terradillos et al, 1997). X-speci®c transcripts and HBx protein declined with age and fell to undetectable levels in adult livers.…”

“…Transgenic expression of the X gene has been shown to induce frequent liver tumors in a transgenic mouse line generated in the CD1 background (Kim et al, 1991). In other murine lines, HBx induced no pathology, but it sensitized liver cells to the carcinogenic e ects of diethylnitrosamine (Dandri et al, 1996;Slagle et al, 1996), and cooperated with c-myc by accelerating the onset of liver tumors (Terradillos et al, 1997). In human HBV carriers, HBx expression is preferentially maintained through the multistage process from preneoplastic nodules to HCC and peritumoral tissues (Su et al, 1998) and X-speci®c mRNAs selectively accumulate in liver tumors from HBsAg-negative patients (Paterlini et al, 1995).…”

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

“…In most integrated subviral DNA, the HBx gene is maintained and transcribed and several studies have now demonstrated both HBx RNA and protein expression in human HCC tumor cells in the absence of HBV replication (Su et al, 1998;Peng et al, 2005). The available in vivo data suggest that HBx expression in transgenic mice likely induces HCC by sensitization of the animals to chemical carcinogens or by altering cellular oncogenes such as c-myc (Terradillos et al, 1997;Madden et al, 2001;Lakhtakia et al, 2003;Hung and Kumar, 2004;Wang et al, 2004a;Zhu et al, 2004;Koo et al, 2005).…”

Hepatitis B virus-X protein upregulates the expression of p21wafl/cipl and prolongs G1→S transition via a p53-independent pathway in human hepatoma cells

“…Hepatitis B virus (HBV) causes acute and chronic liver cell injury and in¯ammation and is closely associated with liver cancer (Chisari, 1996;Kim et al, 1991;Terradillos et al, 1997). Among the four gene products, HBsAg, HBcAg, HBxAg and polymerase encoded by the four ORFs in HBV, HBxAg is a protein, approximately 154 amino acids long, which has been detected with high frequency in liver cells from patients with chronic hepatitis, cirrhosis and liver cancer and might be a prime candidate for mediating the HBV pathologic e ect.…”