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 (TNFalpha) 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.
Department of Morphology and Embryology, and Center of Biotechnology, University of Ferrara, Ferrara, Italy.
Cristina
C
Morelli
Katia
K
Campioni
Cristina
C
Parolin
Giorgio
G
Palù
Mauro
M
Tognon
D015152:Blotting, Northern; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects / Q000235:genetics*; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D014409:Tumor Necrosis Factor-alpha; D020780:Matrix Metalloproteinase 9