Concomitant overexpression of cyclooxygenase-2 in HER-2-positive on Smad4-reduced human gastric carcinomas is associated with a poor patient outcome
Concomitant overexpression of cyclooxygenase-2 in HER-2-positive on Smad4-reduced human gastric carcinomas is associated with a poor patient outcome
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DOI：
10.1158/1078-0432.ccr-0731-03
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发表时间：
2004-10-15
影响因子：
11.5
通讯作者：
Tanigawa, N
中科院分区：
文献类型：
--
作者：
Okano, H;Shinohara, H;Tanigawa, N
目的：环氧化酶-2 （cycloxygenase -2, COX-2）的表达参与胃癌的发生和肿瘤的进展，但COX-2上调的机制尚不清楚。我们研究了两种生长因子信号系统HER-2和转化生长因子(TGF)- β在人胃癌组织中诱导COX-2的作用。实验设计：采用免疫组化方法检测166例晚期胃癌手术标本中COX-2的表达；然后分析COX-2的表达与HER-2、tgf - β和Smad4（一种传递tgf - β信号的细胞内介质）的表达之间可能的相关性。结果：COX-2蛋白在91例（54.8%）肿瘤中过表达；COX-2过表达与分化的组织学类型、深部浸润和淋巴结转移阳性相关。COX-2在her -2阳性肿瘤（22例中有19例，86.4%）和smad4减少的肿瘤（104例中有67例，64.4%）中经常过表达，但与TGF-beta1表达状态无关。COX-2和HER-2的表达水平以及Smad4的降低都与患者预后不良有关。一项多变量分析表明，smad4减少的肿瘤患者中COX-2的过表达预后明显较差。结论：这些结果支持通过HER-2和tgf - β /Smad系统的信号转导可能参与COX-2表达的可能性，并且Smad4的减少可能在tgf - β启动的COX-2过表达中具有部分因果意义，这与胃癌患者预后不良有关。
Purpose: 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.Experimental Design: 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-betal, and Smad4, an intracellular mediator that transmits the TGF-beta signal, were then analyzed.Results: 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 Smad4reduced tumors.Conclusions: 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.