Tatyana Ivanova and Svetlana Vinokurova contributed equally to this study.
Predictive Markers and Cancer Prevention
Frequent hypermethylation of 5′ flanking region of TIMP-2 gene in cervical cancer
Article first published online: 25 NOV 2003
Copyright © 2003 Wiley-Liss, Inc.
International Journal of Cancer
Volume 108, Issue 6, pages 882–886, 1 March 2004
How to Cite
Ivanova, T., Vinokurova, S., Petrenko, A., Eshilev, E., Solovyova, N., Kisseljov, F. and Kisseljova, N. (2004), Frequent hypermethylation of 5′ flanking region of TIMP-2 gene in cervical cancer. Int. J. Cancer, 108: 882–886. doi: 10.1002/ijc.11652
- Issue published online: 2 JAN 2004
- Article first published online: 25 NOV 2003
- Manuscript Accepted: 16 SEP 2003
- Manuscript Revised: 11 SEP 2003
- Manuscript Received: 1 APR 2003
- Russian Foundation of Basic Science. Grant Number: 01-04-49225
- TIMP-2, methylation;
- cervical cancer;
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.