Carcinogenesis Advance Access originally published online on February 3, 2005
Carcinogenesis 2005 26(5):892-899; doi:10.1093/carcin/bgi029
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Carcinogenesis vol.26 no.5 © Oxford University Press 2005; all rights reserved.
Association of Ets-related transcriptional factor E1AF expression with overexpression of matrix metalloproteinases, COX-2 and iNOS in the early stage of colorectal carcinogenesis
First Department of Internal Medicine, Sapporo Medical University, S.-1, W.-16, Chuo-ku, Sapporo 060–8543, Japan and 1 Department of Clinical Laboratory Science, Yamaguchi University School of Medicine, Ube 755–8505, Japan
* To whom correspondence should be addressed. Tel: +81 11 611 2111 (ext.) 3211; Fax: +81 11 611 2282; Email: nosho{at}sapmed.ac.jp
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.
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