Okano Hirokazu, Shinohara Hisashi, Miyamoto Akiko, Takaori Kyoichi, Tanigawa Nobuhiko
Department of General and Gastroenterological Surgery, Osaka Medical College, Osaka, Japan.
Clin Cancer Res. 2004 Oct 15;10(20):6938-45. doi: 10.1158/1078-0432.CCR-0731-03.
The expression of cyclooxygenase-2 (COX-2) is known to be involved in gastric carcinogenesis and tumor progression, but little is known about the mechanisms responsible for the up-regulation of COX-2. We examined the involvement of two growth factor-signaling systems, HER-2 and transforming growth factor (TGF)-beta, in the induction of COX-2 in human gastric cancer tissue.
COX-2 expression was detected by immunohistochemistry in surgical specimens obtained from 166 patients with advanced gastric cancer; possible correlations between the expression of COX-2 and the expression of HER-2, TGF-beta1, and Smad4, an intracellular mediator that transmits the TGF-beta signal, were then analyzed.
COX-2 protein was overexpressed in 91 (54.8%) tumors; COX-2 overexpression was correlated with a differentiated histologic type, deep invasion, and positive lymph node metastasis. COX-2 was frequently overexpressed in HER-2-positive tumors (19 of 22, 86.4%) and in Smad4-reduced tumors (67 of 104, 64.4%) but irrelevant to the TGF-beta1 expression status. The expression levels of COX-2 and HER-2 and the reduction in Smad4 were all associated with a poor patient outcome. A multivariate analysis demonstrated a significantly poor outcome for the concomitant overexpression of COX-2 in patients with Smad4-reduced tumors.
These results support the possibility that signal transduction via HER-2 and the TGF-beta/Smad system may be implicated in COX-2 expression and that the reduction of Smad4 may be, in part, of causal significance in the TGF-beta-initiated overexpression of COX-2, which is associated with a poor prognosis for patients with gastric cancer.
已知环氧合酶 - 2（COX - 2）的表达参与胃癌的发生和肿瘤进展，但关于COX - 2上调的机制知之甚少。我们研究了两种生长因子信号系统，即HER - 2和转化生长因子（TGF）-β，在人胃癌组织中COX - 2诱导中的作用。
通过免疫组织化学检测166例晚期胃癌患者手术标本中COX - 2的表达；然后分析COX - 2表达与HER - 2、TGF - β1和Smad4（一种传递TGF - β信号的细胞内介质）表达之间的可能相关性。
91例（54.8%）肿瘤中COX - 2蛋白过度表达；COX - 2过度表达与组织学分化类型、深度浸润和阳性淋巴结转移相关。COX - 2在HER - 2阳性肿瘤（22例中的19例，86.4%）和Smad4减少的肿瘤（104例中的67例，64.4%）中经常过度表达，但与TGF - β1表达状态无关。COX - 2和HER - 2的表达水平以及Smad4的减少均与患者预后不良相关。多因素分析表明，Smad4减少的患者中COX - 2同时过度表达的预后明显较差。
这些结果支持这样一种可能性，即通过HER - 2和TGF - β/Smad系统的信号转导可能与COX - 2表达有关，并且Smad4的减少可能部分地在TGF - β引发的COX - 2过度表达中具有因果意义，这与胃癌患者的不良预后相关。
