Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma.
We identified that suppressor of cytokine signaling-3 (SOCS-3) gene was aberrantly methylated in its CpG island in three of 10 human hepatocellular carcinoma (HCC) cell lines. SOCS-3 RNA was undetectable in five of the 10 HCC cell lines including the three methylated cell lines, and a demethylating agent, 5-aza-2'-deoxycytidine, reactivated ... SOCS-3 expression in three cell lines tested. The DNA region where we found aberrant DNA methylation includes a signal transducers and activators of transcription (STAT) binding consensus sequence. When the DNA region was used as a promoter, DNA methylation markedly reduced promoter activity. SOCS-3 was also aberrantly methylated in six of 18 primary HCC samples. SOCS-3 expression was reduced in three of the three methylated and one of the three unmethylated primary samples examined. Restoration of SOCS-3 in cells lacking SOCS-3 expression suppressed STAT3 phosphorylation and cell growth. We found that IL-6 acted as a growth factor in HCC cells. Inhibition of SOCS-3 expression in cells whose growth was induced by IL-6 enhanced STAT3 phosphorylation and cell growth. In addition, AG490, a chemical JAK2 inhibitor, suppressed cell growth and downregulated STAT3 phosphorylation, but not FAK phosphorylation. We also found that SOCS-3 physically interacted with phosphorylated FAK and Elongin B in HCC cells. Restoration of SOCS-3 decreased FAK phosphorylation as well as FAK protein level. Inhibition of SOCS-3 expression increased FAK phosphorylation, resulting in enhancement of cell migration. These data indicate that SOCS-3 negatively regulates cell growth and cell motility by inhibiting Janus kinase (JAK)/STAT and FAK signalings in HCC cells. Thus, loss of SOCS-3 by the associated DNA methylation confers cells advantage in growth and migration.
Mesh Terms:
Carcinoma, Hepatocellular, Cell Division, Cell Line, Tumor, Cell Movement, DNA Methylation, DNA-Binding Proteins, Focal Adhesion Kinase 1, Focal Adhesion Protein-Tyrosine Kinases, Gene Silencing, Humans, JNK Mitogen-Activated Protein Kinases, Liver Neoplasms, Phosphorylation, Protein-Tyrosine Kinases, Repressor Proteins, STAT1 Transcription Factor, Signal Transduction, Suppressor of Cytokine Signaling Proteins, Trans-Activators, Transcription Factors
Carcinoma, Hepatocellular, Cell Division, Cell Line, Tumor, Cell Movement, DNA Methylation, DNA-Binding Proteins, Focal Adhesion Kinase 1, Focal Adhesion Protein-Tyrosine Kinases, Gene Silencing, Humans, JNK Mitogen-Activated Protein Kinases, Liver Neoplasms, Phosphorylation, Protein-Tyrosine Kinases, Repressor Proteins, STAT1 Transcription Factor, Signal Transduction, Suppressor of Cytokine Signaling Proteins, Trans-Activators, Transcription Factors
Oncogene
Date: Sep. 22, 2005
PubMed ID: 16007195
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