Epigenetic downregulation of the suppressor of cytokine signaling 1 (Socs1) gene is associated with the STAT3 activation and development of hepatocellular carcinoma induced by methyl-deficiency in rats.
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.
Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079, USA.
Tetyana V
TV
Bagnyukova
Volodymyr P
VP
Tryndyak
Levan
L
Muskhelishvili
Sharon A
SA
Ross
Frederick A
FA
Beland
Igor P
IP
Pogribny
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D004032:Diet; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D008715:Methionine / Q000172:deficiency*; D008745:Methylation; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
D010982:Platelet-Derived Growth Factor; D050796:STAT3 Transcription Factor; C491589:Socs1 protein, rat; C494088:Stat3 protein, rat; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016212:Transforming Growth Factor beta; D008715:Methionine; D017479:Receptors, Platelet-Derived Growth Factor