Molecular mechanisms of hepatocarcinogenesis in transgenic mouse models of liver cancer.

Overexpression of c-myc and transforming growth factor-alpha (TGF-alpha) has been frequently observed in human hepatocellular carcinoma (HCC),suggesting a pivotal role played by these protooncogenes in liver oncogenesis. In order to investigate the molecular events underlying human hepatic malignant transformation, we have generated c-myc and c-myc/ TGF-alpha transgenic mice that are prone to liver cancer. These transgenic mice develop HCCs with different incidence, kinetics and histopathological features. Indeed, co-expression of c-myc and TGF-alpha transgenes results in a dramatic synergistic effect on liver tumor development when compared with respective single transgenic lines, including a shorter latency period and a more aggressive phenotype. The more malignant histopathological features characteristic of c-myc/ TGF-alpha HCCs are the result of the increased proliferation and reduced apoptosis in this model of liver cancer when compared with single parental lines. Accordingly, c-myc and c-myc/l TGF-alpha transgenic mice display a different molecular pathogenesis of HCC. Importantly, the genetic and molecular mechanisms that are involved in c-myc and c-myc/ TGF-alpha liver cancer development are major oncogenic events in human hepatocarcinogenesis, indicating that these mouse models represent a useful tool to dissect and elucidate the molecular basis of human HCC.