title: Antiproliferative effect of SOCS-1 through the suppression of STAT3 and p38 MAPK activation in gastric cancer cells.
abstract: 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.
authors.affiliation: Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Souma
authors.forename: Toshirou
authors.initials: T
authors.lastname: Nishida
authors.forename: Satoshi
authors.initials: S
authors.lastname: Serada
authors.forename: Kota
authors.initials: K
authors.lastname: Iwahori
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Takahashi
authors.forename: Minoru
authors.initials: M
authors.lastname: Fujimoto
authors.forename: Barry
authors.initials: B
authors.lastname: Ripley
authors.forename: Kiyokazu
authors.initials: K
authors.lastname: Nakajima
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Miyazaki
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sawa
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Naka
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018899:CpG Islands; D019175:DNA Methylation; D004789:Enzyme Activation; D015316:Genetic Therapy; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D019947:Receptors, Interleukin-6 / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D013274:Stomach Neoplasms / Q000209:etiology / Q000473:pathology / Q000628:therapy*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D019947:Receptors, Interleukin-6; C108944:SOCS1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D019869:Phosphatidylinositol 3-Kinases; D048051:p38 Mitogen-Activated Protein Kinases