Stromelysin-1 promoter mutations impair gelatinase B activation in high microsatellite instability sporadic colorectal tumors.
Colorectal cancers from the mutator phenotype pathway display distinctive pathological features 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.
Morán
Alberto
A
Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain.
Iniesta
Pilar
P
de Juan
Carmen
C
González-Quevedo
Rosa
R
Sánchez-Pernaute
Andrés
A
Díaz-Rubio
Eduardo
E
Ramón y Cajal
Santiago
S
Torres
Antonio
A
Balibrea
Jose Luis
JL
Benito
Manuel
M
D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D004273:DNA, Neoplasm / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis / Q000235:genetics*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D018895:Microsatellite Repeats / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D009367:Neoplasm Staging; D011401:Promoter Regions, Genetic
D004273:DNA, Neoplasm; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9