Association of ets‐related transcriptional factor E1AF expression with tumour progression and overexpression of MMP‐1 and matrilysin in human colorectal cancer

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Abstract
Expression of E1AF/PEA3 (ETV4), an ets family transcription factor, has been implicated in the invasive potential of several cancer cell lines through induction of matrix metalloproteinase (MMP) expression. The aim of this study was to examine E1AF mRNA expression and to determine whether it is correlated with progression of, and/or MMP expression in, human colorectal cancer. Using the semi‐quantitative reverse transcriptase‐polymerase chain reaction (RT‐PCR), 100 colorectal cancer tissues were analysed for E1AF mRNA expression. Expression of ER81 (ETV1) and ERM (ETV5), the other two members of the PEA3 subfamily, and Ets‐1 and Ets‐2 was also analysed. The results were correlated with clinicopathological characteristics and MMP expression. Immunohistochemical analysis and an in vitro invasion assay were also performed. E1AF mRNA expression was detected in 62% of the 100 colorectal cancer tissues, but was undetectable or only faintly detected in adjacent non‐tumour tissues. E1AF mRNA was detected in all of the ten liver metastases from colorectal cancers. E1AF expression correlated significantly with depth of invasion, lymphatic and venous invasion, lymph node and distant metastasis, advance in pathological tumour–node–metastasis stage, and recurrence. Patients with E1AF‐positive tumours had significantly shorter overall and disease‐free survival periods than did those with E1AF‐negative tumours (p < 0.0001 and p < 0.0001, respectively). E1AF expression retained its significant predictive value for overall and disease‐free survival in multivariate analysis that included conventional clinicopathological factors (p = 0.0066 and p = 0.0109, respectively). Among the MMPs analysed, expression of MMP‐1 and matrilysin correlated significantly with E1AF expression. In contrast, expression of ER81 and ERM did not correlate with clinicopathological characteristics or the expression of these MMPs. Immunohistochemical expression of E1AF was predominantly observed at the invasive front, where the expression of MMP‐1 and matrilysin and nuclear β‐catenin expression were often co‐localized. Antisense E1AF‐transfected HT‐29 colon cancer cells expressed reduced levels of MMP‐1 and matrilysin and were less invasive in vitro than neo‐transfected HT‐29 cells. The results of this study suggest that E1AF, the expression of which is closely correlated with the expression of MMP‐1 and matrilysin, plays a key role in the progression of colorectal cancer. Copyright © 2003 John Wiley & Sons, Ltd.