Role of matrix metalloproteinases in colorectal carcinogenesis.

Abstract

To measure coexpression of matrix metalloproteinase (MMP)-2, MMP-7, and MMP-9 genes by real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) in benign and malignant phases of colorectal carcinogenesis. Matrix metalloproteinases degrade and remodel the extracellular matrix and have been implicated in facilitating carcinoma cells to invade and metastasize. MMP-2, MMP-7, and MMP-9 have been shown to be overexpressed in various carcinomas; however, simultaneous examination of these enzymes in human normal mucosa, adenoma, and carcinoma has not been performed to date. Between January 1, 1998, and June 15, 2000, 40 patients underwent colectomy and harvest and snap-freezing of normal mucosa, adenoma, and carcinoma. Five patients had adenoma and carcinoma in the same specimen; 35 had either adenoma (n = 6) or carcinoma (n = 29). Taqman qRT-PCR methodology was used to measure MMP gene copy number and normalized to beta-actin RNA expression. The mean age was 62 +/- 4 years, with 22 men and 18 women. One fifth of the adenomas exhibited severe dysplasia. MMP-7 gene expression was significantly increased in adenomas (43 times normal mucosa) but did not increase further in carcinomas (50 times normal mucosa). MMP-2 and MMP-9 were not different in adenomas (1.8 and 1.4 times normal mucosa, respectively) but were elevated in carcinomas (2.2 and 1.8 times normal mucosa, respectively). There was no correlation between size or dysplasia in adenomas or AJCC stage in carcinomas and MMP gene expression. Overexpression of MMP-7 is an early event in the adenoma-to-carcinoma pathway, and expression does not appear to increase further in carcinomas. MMP-2 and MMP-9 appear to be primarily overexpressed in carcinomas. This may be one mechanism by which adenoma cells gain the ability to invade and carcinoma cells to metastasize.