TY - JOUR
T1 - Effects of 5-Aza-2′ -deoxycytidine on matrix metalloproteinase expression and pancreatic cancer cell invasiveness
AU - Sato, Norihiro
AU - Maehara, Naoki
AU - Su, Gloria H.
AU - Goggins, Michael
PY - 2003/2/19
Y1 - 2003/2/19
N2 - 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.
AB - 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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U2 - 10.1093/jnci/95.4.327
DO - 10.1093/jnci/95.4.327
M3 - Article
C2 - 12591989
AN - SCOPUS:0037453906
SN - 0027-8874
VL - 95
SP - 327
EP - 331
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 4
ER -