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Frequent hypermethylation of 5′ flanking region of TIMP-2 gene in cervical cancer

✍ Scribed by Tatyana Ivanova; Svetlana Vinokurova; Anatolii Petrenko; Ernest Eshilev; Nina Solovyova; Fjodor Kisseljov; Natalia Kisseljova

Publisher
John Wiley and Sons
Year
2004
Tongue
French
Weight
172 KB
Volume
108
Category
Article
ISSN
0020-7136

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✦ Synopsis

Abstract

Tissue inhibitor of metalloproteinase‐2 (TIMP‐2) is an endogenous inhibitor of matrix metalloproteinases (MMPs). This multifunctional protein regulates activities of MMPs and possesses growth promoting effect in cell culture, anti‐tumoral, anti‐apoptotic and anti‐angiogenic effects in animal model systems in vivo. It has been shown that this gene is downregulated in cervical carcinomas. The mechanism of inhibition of TIMP‐2 expression remains obscure. We have examined whether aberrant DNA methylation of the 5′CpG island of the TIMP‐2 gene is involved in its inhibition during cervical carcinogenesis. Bisulfite‐modified DNA sequencing and MSP assay showed aberrant methylation of TIMP‐2 5′‐CpG island in 17 of 36 (47%) invasive cervical carcinomas and in 2 of 3 cervical cancer cell lines. TIMP‐2 gene was mostly unmethylated in the morphologically normal tissues adjacent to the tumors, whereas methylated alleles of this gene were found in 4 samples. Each tumor and each cell line DNA was characterized by unique methylation pattern, however a discrete region of TIMP‐2 CpG island upstream to the transcription start site was densely methylated in all hypermethylated DNA samples examined. The expression of TIMP‐2 mRNA can be restored in the cell lines, in which this discrete region of TIMP‐2 CpG island is methylated, by treatment with demethylating agents, 5‐azacytidine and 5‐aza‐2′‐deoxycytidine. Our data suggest that the aberrant methylation of TIMP‐2 favors the development of primary cervical tumors. We describe for the first time the aberrant hypermethylation of TIMP‐2 gene in human cancer. © 2003 Wiley‐Liss, Inc.

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