The members of the
platelet-derived growth factor (PDGF) and the
transforming growth factor-beta (
TGFbeta) pathways are important in the induction of
liver fibrosis and
cirrhosis; however, their role in the subsequent progression to
hepatocellular carcinoma (HCC) remains elusive. Our study provides new insights into mechanisms of dysregulation of PDGFs,
TGFbeta and signal transducer and activator of transcription (STAT) pathways in the pathogenesis of methyl-deficient rodent liver
carcinogenesis, a remarkably relevant model to the development of HCC in humans. We demonstrated a progressive increase in the Pdgfs and
TGFbeta expression in preneoplastic tissue and liver
tumors indicating their promotional role in
carcinogenesis, particularly in progression of
liver fibrosis and
cirrhosis. However, activation of the STAT3 occurred only in fully developed HCC and was associated with downregulation of the Socs1 gene. The inhibition of the Socs1 expression in HCC was associated with an increase in
histone H3 lysine 9, H3
lysine 27, and H4
lysine 20 trimethylation at the Socs1 promoter, but not with promoter methylation. The results of our study suggest the following model of events in hepatocarcinogenesis: during early stages, overexpression of the Socs1 effectively inhibits
TGFbeta- and PDGF-induced STAT3 activation, whereas, during the advanced stages of hepatocarcinogenesis, the Socs1 downregulation resulted in loss of its ability to attenuate the signal from the upregulated
TGFbeta and PDGFs leading to oncogenic STAT3 activation and malignant cell transformation. This model illustrates that the Socs1 acts as classic
tumor suppressor by preventing activation of the STAT3 and downregulation of Socs1 and consequent activation of STAT3 may be a crucial events leading to formation of HCC.