Document Detail


Anti-proliferative effect of SOCS-1 through the suppression of STAT3 and p38 MAPK activation in gastric cancer cells.
MedLine Citation:
PMID:  22095154     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Inflammation is a crucial driving force in the development of gastric cancers (GC). 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. This 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 anti-proliferative 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.
Authors:
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
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-11-18
Journal Detail:
Title:  International journal of cancer. Journal international du cancer     Volume:  -     ISSN:  1097-0215     ISO Abbreviation:  -     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-11-18     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0042124     Medline TA:  Int J Cancer     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2011 UICC.
Affiliation:
Department of Surgery Osaka University Graduate School of Medicine, Osaka, Japan.
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