Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
Int J Cancer. 2012 Sep 15;131(6):1287-96. doi: 10.1002/ijc.27350. Epub 2011 Dec 14.
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.
炎症是胃癌（GC）发展的关键驱动因素。因此，尽管其机制仍不清楚，但STAT3 转录因子在调节炎症和肿瘤发生方面起着至关重要的作用，在 GC 中通常被检测到持续激活。细胞因子信号转导抑制因子-1（SOCS-1）是促炎细胞因子信号转导的负调节剂，SOCS-1 基因甲基化在包括 GC 在内的各种癌症中经常被检测到。然而，SOCS-1 甲基化在 GC 细胞中的意义仍未被探索。我们的研究旨在评估 SOCS-1 在 GC 细胞增殖中的作用及其对 GC 细胞信号通路的影响。在五种 GC 细胞系中，所有细胞系的 SOCS-1 基因均发生甲基化，并且在两种细胞系（NUGC-3 和 AGS）中检测到内源性 IL-6 产生的 STAT3 磷酸化升高。出乎意料的是，抗 IL-6R 抗体既不能抑制 NUGC-3 和 AGS 细胞的增殖，也不能抑制 STAT3 磷酸化。相比之下，腺病毒载体（AdSOCS-1）强制表达 SOCS-1 可显著抑制 NUGC-3 和 AGS 细胞体外的 STAT3 磷酸化和增殖。有趣的是，SOCS-1 的增殖抑制作用不仅归因于 STAT3 的抑制，还归因于 p38 MAPK 活性的抑制，并且 JAK/STAT 和 p38 MAPK 信号的化学抑制剂可有效抑制这些 GC 细胞的增殖。此外，体内 AdSOCS-1 治疗显著抑制了异种移植模型中的 GC 增殖。这些结果表明，SOCS-1 基因甲基化是 GC 发展的关键步骤，强制表达 SOCS-1 可能代表治疗 GC 的一种新的治疗方法。
