This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Morán, A. Articles by Benito, M. Search for Related Content PubMed PubMed Citation Articles by Morán, A. Articles by Benito, M.

Impairment of Stromelysin-1 Transcriptional Activity by Promoter Mutations in High Microsatellite Instability Colorectal Tumors

Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense, Madrid, Spain

Requests for reprints: Manuel Benito, Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain. Phone: 34-91-394-1777; Fax: 34-91-394-1779; E-mail: benito{at}farm.ucm.es.

Colorectal tumorigenesis is characterized by the sequential inactivation of a series of tumor suppressor genes (microsatellite-stable tumors) and genetic or epigenetic alterations in mismatch repair genes in nonpoliposic hereditary tumours and 13% to 15% of sporadic colorectal cancer [high microsatellite instability (MSI-H) tumors]. We hypothesized a molecular mechanism for MSI-H colorectal tumors related to matrix metalloproteinase 3 (MMP-3) promoter mutations, down-regulation of MMP-3 expression, and impairment of MMP-9 activation. We have now analyzed the 2.2-kb full MMP-3 promoter to assess the mutation distribution. The mutations found are restricted to the polymorphic region that includes the zinc-binding protein (ZBP-89) binding element. To show that these alterations were the cause of the low expression of this gene, we have generated three constructs with different MMP-3 promoters (wild type and two mutants) and we have expressed them in SW480 human colorectal cells. The basal transcriptional activity of wild-type MMP-3 promoter was much higher than the mutants activity. In addition, 12-O-tetradecanoylphorbol-13-acetate (TPA)–induced transcriptional activity of wild-type MMP-3 promoter was 10-fold higher than the mutants activity. Dexamethasone inhibited the basal transcriptional activity of wild-type MMP-3 promoter and of the two mutants found in the MSI-H subgroup of colorectal tumors. Significantly, dexamethasone almost completely blunted the TPA-induced effect on wild-type MMP-3 promoter transcriptional activity and on the mutants, even below their basal activity. Our data show that mutations found in the polymorphic region of the MMP-3 promoter from MSI-H colorectal tumors impair its basal and induced transcriptional activity, which may contribute to their better clinical outcome.

This article has been cited by other articles:

				K. Imai and H. Yamamoto Carcinogenesis and microsatellite instability: the interrelationship between genetics and epigenetics Carcinogenesis, April 1, 2008; 29(4): 673 - 680. [Abstract] [Full Text] [PDF]

				P. Ortega, A. Moran, C. de Juan, C. Frias, S. Hernandez, J.-A. Lopez-Asenjo, A. Sanchez-Pernaute, A. Torres, P. Iniesta, and M. Benito Differential Wnt Pathway Gene Expression and E-Cadherin Truncation in Sporadic Colorectal Cancers with and without Microsatellite Instability Clin. Cancer Res., February 15, 2008; 14(4): 995 - 1001. [Abstract] [Full Text] [PDF]