Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma

Yasuharu Niwa, Hiroaki Kanda, Yuko Shikauchi, Akio Saiura, Kenichi Matsubara, Tomoyuki Kitagawa, Junji Yamamoto, Takahiko Kubo, Hirohide Yoshikawa

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)6406-6417
Number of pages12
JournalOncogene
Volume24
Issue number42
DOIs
Publication statusPublished - Sep 22 2005
Externally publishedYes

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Janus Kinases
Transducers
Methylation
Cell Movement
Hepatocellular Carcinoma
Cytokines
Growth
Phosphorylation
DNA Methylation
Cell Line
decitabine
Interleukin-6
Growth Inhibitors
CpG Islands
DNA
Consensus Sequence

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Niwa, Y., Kanda, H., Shikauchi, Y., Saiura, A., Matsubara, K., Kitagawa, T., ... Yoshikawa, H. (2005). Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma. Oncogene, 24(42), 6406-6417. https://doi.org/10.1038/sj.onc.1208788

Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma. / Niwa, Yasuharu; Kanda, Hiroaki; Shikauchi, Yuko; Saiura, Akio; Matsubara, Kenichi; Kitagawa, Tomoyuki; Yamamoto, Junji; Kubo, Takahiko; Yoshikawa, Hirohide.

In: Oncogene, Vol. 24, No. 42, 22.09.2005, p. 6406-6417.

Research output: Contribution to journalArticle

Niwa, Y, Kanda, H, Shikauchi, Y, Saiura, A, Matsubara, K, Kitagawa, T, Yamamoto, J, Kubo, T & Yoshikawa, H 2005, 'Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma', Oncogene, vol. 24, no. 42, pp. 6406-6417. https://doi.org/10.1038/sj.onc.1208788
Niwa, Yasuharu ; Kanda, Hiroaki ; Shikauchi, Yuko ; Saiura, Akio ; Matsubara, Kenichi ; Kitagawa, Tomoyuki ; Yamamoto, Junji ; Kubo, Takahiko ; Yoshikawa, Hirohide. / Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma. In: Oncogene. 2005 ; Vol. 24, No. 42. pp. 6406-6417.
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AU - Saiura, Akio

AU - Matsubara, Kenichi

AU - Kitagawa, Tomoyuki

AU - Yamamoto, Junji

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AU - Yoshikawa, Hirohide

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AB - 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.

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