Association of Ets-related transcriptional factor E1AF expression with overexpression of matrix metalloproteinases, COX-2 and iNOS in the early stage of colorectal carcinogenesis
Association of Ets-related transcriptional factor E1AF expression with overexpression of matrix metalloproteinases, COX-2 and iNOS in the early stage of colorectal carcinogenesis
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DOI：
10.1093/carcin/bgi029
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发表时间：
2005-05-01
期刊：
影响因子：
4.7
通讯作者：
Imai, K
中科院分区：
文献类型：
--
作者：
Nosho, K;Yoshida, M;Imai, K
现在越来越清楚的是，基质金属蛋白酶(MMPs)在肿瘤的发生和生长中起着关键作用。MMPs在包括结直肠腺瘤在内的多种癌前组织中均有过表达。目前对腺瘤组织中MMPs过度表达的机制知之甚少。E1AF是一种ETS家族转录因子，在MMPs和环氧合酶-2(COX-2)的表达中起重要作用。本研究的目的是检测E1AF在人结直肠腺瘤和粘膜下癌(PT1)中的表达，并探讨其与MMPs、COX-2和诱导型一氧化氮合酶(INOS)表达的相关性。应用半定量RT-PCR方法检测了90例结直肠癌组织中E1AF、MMPs、COX-2和iNOS的表达，其中腺瘤63例，癌27例。同时进行免疫组织化学分析和体外转染实验。在90例结直肠肿瘤中，43例(47.8%)表达E1AF基因。E1AF的过度表达与组织病理学显著相关。E1AF的表达与基质金属蛋白酶-1和基质金属蛋白酶-7的表达显著相关。在90例结直肠肿瘤中，COX-2和iNOS的高表达分别为42.2%和66.7%。COX-2与肿瘤的大小、性别、组织病理学和E1AF显著相关。INOS与肿瘤大小、组织病理学、E1AF、COX-2显著相关。免疫组织化学显示E1AF表达与COX-2、iNOS表达呈正相关。Northern印迹分析显示，E1AF对结肠癌细胞株COX-2表达的影响以及iNOS对E1AF/COX-2表达的影响。提示E1AF与基质金属蛋白酶-1、基质金属蛋白酶-7、环氧合酶-2、诱导型一氧化氮合酶在结直肠癌的早期发生中起重要作用。
It is now becoming clear that matrix metalloproteinases (MMPs) play a key role in tumor development and growth. MMPs are overexpressed in a variety of premalignant tumor tissues, including colorectal adenoma. Little is known about the mechanisms underlying the overexpression of MMPs in adenoma tissues. E1AF, an Ets family transcriptional factor, has been shown to play an important role in the expression of MMPs and cyclooxygenase-2 (COX-2) in advanced colorectal cancers. The aim of this study was to examine the E1AF expression and determine whether it is correlated with the expression of MMPs, COX-2 and inducible nitric oxide synthase (iNOS) in human colorectal adenoma and submucosal cancer (pT1). Using the semi-quantitative RT-PCR, 90 colorectal tumors, including 63 adenomas and 27 cancers (pT1), were analyzed for the expression of E1AF, MMPs, COX-2 and iNOS. Immunohistochemical analysis and in vitro transfection assays were also performed. E1AF mRNA was detected in 43 (47.8%) of the 90 colorectal tumors. E1AF overexpression was significantly correlated with histopathology. E1AF expression was correlated significantly with the expression of MMP-1 and MMP-7. Overexpression of COX-2 and iNOS mRNA expression was observed in 42.2% and 66.7% of the 90 colorectal tumors, respectively. COX-2 was correlated significantly with size, gender, histopathology and E1AF. iNOS was correlated significantly with size, histopathology, E1AF and COX-2. The correlation of E1AF expression with COX-2 and iNOS expression was also demonstrated by immunohistochemistry. Northern blot analysis of transfectants showed the effect of E1AF on COX-2 expression as well as iNOS on E1AF/COX-2 expression in colon cancer cell lines. The results suggest that E1AF, in conjunction with the expression of MMP-1, MMP-7, COX-2 and iNOS, plays an important role in the early stage of colorectal carcinogenesis.