Molecular Pathogenesis of Hepatocellular Carcinoma: Altering Transforming Growth Factor-beta Signaling in Hepatocarcinogenesis

Hepatocellular carcinoma (HCC) occurs subsequent to liver injury, where regenerative hepatocytes develop into a dysplastic nodule and then early HCC, supporting the multistep hepatocarcinogenesis theory. Molecular alterations such as the p53 mutation, p16 gene silencing, and AKT signaling activation are found in the late stage of HCC progression. The overexpression of some marker molecules is observed at the early stage. Transforming growth factor-beta (TGF-beta), a potent inhibitor of cell proliferation, is frequently overexpressed in HCC, although the role of TGF-beta signaling during HCC development remains controversial. We previously reported that HCC cells show TGF-beta receptor-dependent growth inhibition in response to TGF-beta. Also, reduced TGF-beta receptor II in HCC correlates with intrahepatic metastasis and shorter time-to-recurrence, suggesting a role of TGF-beta signaling in tumor suppression. In contrast, TGF-beta overexpression in HCC is known to correlate with malignant potential, suggesting a role in tumor promotion. Enhanced formation of stroma is a feature of advanced HCC, and TGF-beta also promotes the proliferation of stromal fibroblasts. The microenvironment produced via tumor-stromal interactions may be the key to the modulation of the dual roles of TGF-beta signaling in HCC progression. Copyright (C) 2011 S. Karger AG, Basel