Activity of the Matrix Metalloproteinase‐9 Promoter in Human Normal and Tumor Cells

Matrix metalloproteinases (MMPs) belong to a family of proteins essential for those processes involving extracellular matrix degradation, such as embryonic development, morphogenesis, and tissue resorption and remodeling. Some members of this family play a crucial role also in tumor invasion. Most notably, MMP‐9 is expressed in invasive tumors, and represents a key protein in brain tumor progression, whereas it is not expressed in adult normal tissues. The expression of the MMP‐9, like other members of the family, is transcriptionally regulated. We, therefore, postulated that the MMP‐9 promoter could be useful in driving selective expression of exogenous genes in tumor cells. This represents a key feature for gene therapy applications, since currently employed viral promoters induce severe organ toxicity, limiting the clinical benefits. In this study, we investigated the activity of the MMP‐9 promoter in driving exogenous gene expression in human cell lines. High levels of reporter gene expression were detected in tumor derived cell lines, whereas the MMP‐9 promoter activity in non‐tumor cells was negligible. Furthermore, we show that tumor necrosis factor alpha (TNFα) is able to enhance considerably the MMP‐9 promoter activity only in tumor cells. Since recent studies have indicated that MMP‐9 enzymatic activity is detectable in the blood, it would be possible to screen potential responsive patients for a tumor gene therapy approach based on the MMP‐9 promoter. Taken together these data suggest that MMP‐9 promoter has the characteristics for transcritpionally targeted and inducible gene therapy applications. J. Cell. Physiol. 199: 126–133, 2004© 2003 Wiley‐Liss, Inc.