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Stromelysin-1 Promoter Mutations Impair Gelatinase B Activation in High Microsatellite Instability Sporadic Colorectal Tumors¹

Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, 28040 Madrid [A. M., P. I., C. d. J., R. G-Q., M. B.]; Servicios de Cirugía [A. S-P., A. T., J. L. B.] and Oncología [E. D-R.], Hospital Clínico "San Carlos," 28040 Madrid; and Servicio de Anatomía Patológica, Hospital Puerta de Hierro, 28035 Madrid [S. R. y C.], Spain

Colorectal cancers from the mutator phenotype pathway display distinctive pathologicalfeatures and confer a lesser aggressiveness than colorectal adenocarcinomas originated by the suppressor pathway. The goal of this work was to test whether tumors developed through the mutator pathway could show a decrease in matrix metalloproteinase (MMP) activity. We evaluated levels and activity of gelatinase A (MMP-2) and gelatinase B (MMP-9), as well as stromelysin-1 (MMP-3) expression in 101 sporadic colorectal tumors in consideration of the microsatellite instability (MSI) status of the groups. Gelatinases were analyzed by ELISA and zymography. The MMP-3 study was performed by real-time quantitative PCR. MMP-9 total levels were significantly higher in MSI-H tumors. However, levels of the active MMP-9 form were significantly much lower in this group of tumors. Data from real-time quantitative PCR indicated that levels of MMP-3 for MSI-L/MSS tumors were much higher as compared with those observed in MSI-H cancers (P = 0.033). Moreover, all MSI-H tumors showed nucleotide insertions and/or deletions in MMP-3 promoter. These mutations were not observed in the group of MSI-L/MSS tumors. Our data indicate that the MMP-3 promoter constitutes a novel target of the defective mismatch repair machinery in sporadic colorectal tumors, resulting in a dramatic decrease in the levels of the active MMP-9 form, which may result in a lessened capacity for invasion.

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