Antiproliferative effect of SOCS-1 through the suppression of STAT3 and p38 MAPK activation in gastric cancer cells

Yoshihito Souma, Toshirou Nishida, Satoshi Serada, Kota Iwahori, Tsuyoshi Takahashi, Minoru Fujimoto, Barry Ripley, Kiyokazu Nakajima, Yasuaki Miyazaki, Masaki Mori, Yuichiro Doki, Yoshiki Sawa, Tetsuji Naka

研究成果: Contribution to journalArticle査読

43 被引用数 (Scopus)

抄録

Inflammation is a crucial driving force in the development of gastric cancers (GCs). Accordingly, persistent activation of STAT3, a transcription factor pivotal in regulating both inflammation and oncogenesis, is often detected in GC, although its mechanism remains elusive. Suppressor of cytokine signaling-1 (SOCS-1) is a negative regulator of proinflammatory cytokine signaling and SOCS-1 gene methylation is frequently detected in various cancers including GC. However, the significance of SOCS-1 methylation in GC cells remains unexplored. Our study is undertaken to evaluate the role of SOCS-1 in GC cell proliferation and its effect on signaling pathways in GC cells. Among five GC cell lines, SOCS-1 gene was methylated in all cell lines and constitutive STAT3 phosphorylation with elevated endogenous IL-6 production was detected in two cell lines (NUGC-3 and AGS). Unexpectedly, anti-IL-6R antibody inhibited neither cell proliferation nor STAT3 phosphorylation in NUGC-3 and AGS. In contrast, enforced SOCS-1 expression by adenoviral vector (AdSOCS-1) markedly suppressed STAT3 phosphorylation and proliferation of NUGC-3 and AGS cells in vitro. Interestingly, the antiproliferative effect of SOCS-1 was attributable not only to the inhibition of STAT3 but also to that of p38 MAPK activity, and chemical inhibitors of JAK/STAT and p38 MAPK signaling effectively suppressed proliferation of these GC cells. Furthermore, treatment with AdSOCS-1 in vivo significantly suppressed GC proliferation in a xenograft model. These results suggest that SOCS-1 gene methylation is a critical step in the development of GC, and enforced expression of SOCS-1 may represent a novel therapeutic approach for the treatment of GC.

本文言語英語
ページ(範囲)1287-1296
ページ数10
ジャーナルInternational Journal of Cancer
131
6
DOI
出版ステータス出版済み - 9 15 2012

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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