© 2003 by Oxford University Press
Journal of the National Cancer Institute, Vol. 95, No. 4, 327-330,
February 19, 2003
© 2003 Oxford University Press
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Effects of 5-Aza-2'-deoxycytidine on Matrix Metalloproteinase Expression and Pancreatic Cancer Cell Invasiveness
Affiliation of authors: N. Sato, N. Maehara (Department of Pathology), G. H. Su (Departments of Pathology and Oncology), M. Goggins (Departments of Pathology, Oncology, and Medicine), The Johns Hopkins Medical Institutions, Baltimore, MD.
Correspondence to: Michael Goggins, M.D., Departments of Pathology, Oncology, and Medicine, The Johns Hopkins Medical Institutions, 632 Ross Bldg., 720 Rutland Ave., Baltimore, MD 21205 (e-mail: mgoggins{at}jhmi.edu).
ABSTRACT
To investigate whether DNA methylation and the invasive phenotype of pancreatic adenocarcinoma are associated, we studied the role of methylation in the transcriptional regulation of several matrix metalloproteinases (MMPs) and the effect of 5-aza-2'-deoxycytidine (5Aza-dC), an inhibitor of DNA methylation, on the invasive behavior of pancreatic cancer cells. Using the Boyden chamber in vitro invasion assay, we found a statistically significant increase in invasive potential in four of five pancreatic cancer cell lines after treatment with 5Aza-dC. This enhanced invasiveness was associated with the induction of mRNAs for one or more MMPs critical for tumor invasion, including MMP-1, -2, -3, -7, -9, and -14. Addition of an MMP inhibitor (GM6001, GM1489, doxycycline, or tissue inhibitor of metalloproteinase 2) blocked the 5Aza-dC-induced increase in the number of invading cells. As shown by a methylation-specific polymerase chain reaction, 5' CpG sites in MMP-2, -7, and -9 genes were partially or completely methylated in cell lines that expressed little or no corresponding mRNAs. Thus, DNA methylation influences the expression of MMP genes, and use of methylation inhibitors may stimulate the invasion of pancreatic cancer by reactivating invasion-promoting genes.
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