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Promoter Hypermethylation Contributes to Frequent Inactivation of a Putative Conditional Tumor Suppressor Gene Connective Tissue Growth Factor in Ovarian Cancer

Kikuchi, Ryoko, Tsuda, Hitoshi, Kanai, Yae, Kasamatsu, Takahiro, Sengoku, Kazuo, Hirohashi, Setsuo, Inazawa, Johji, Imoto, Issei·2007·Cancer Research
DOI 10.1158/0008-5472.can-06-4567

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Abstract

Connective tissue growth factor (CTGF) is a secreted protein belonging to the CCN family, members of which are implicated in various biological processes. We identified a homozygous loss of CTGF (6q23.2) in the course of screening a panel of ovarian cancer cell lines for genomic copy number aberrations using in-house array-based comparative genomic hybridization. CTGF mRNA expression was observed in normal ovarian tissue and immortalized ovarian epithelial cells but was reduced in many ovarian cancer cell lines without its homozygous deletion (12 of 23 lines) and restored after treatment with 5-aza 2′-deoxycytidine. The methylation status around the CTGF CpG island correlated inversely with the expression, and a putative target region for methylation showed promoter activity. CTGF methylation was frequently observed in primary ovarian cancer tissues (39 of 66, 59%) and inversely correlated with CTGF mRNA expression. In an immunohistochemical analysis of primary ovarian cancers, CTGF protein expression was frequently reduced (84 of 103 cases, 82%). Ovarian cancer tended to lack CTGF expression more frequently in the earlier stages (stages I and II) than the advanced stages (stages III and IV). CTGF protein was also differentially expressed among histologic subtypes. Exogenous restoration of CTGF expression or treatment with recombinant CTGF inhibited the growth of ovarian cancer cells lacking its expression, whereas knockdown of endogenous CTGF accelerated growth of ovarian cancer cells with expression of this gene. These results suggest that epigenetic silencing by hypermethylation of the CTGF promoter leads to a loss of CTGF function, which may be a factor in the carcinogenesis of ovarian cancer in a stage-dependent and/or histologic subtype-dependent manner. [Cancer Res 2007;67(15):7095–105]

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Metadata

Authors
Kikuchi, R., Tsuda, H., Kanai, Y., Kasamatsu, T., Sengoku, K., Hirohashi, S., Inazawa, J., & Imoto, I.
Affiliations
  • 1Department of Molecular Cytogenetics, Medical Research Institute and School of Biomedical Science,
  • 4Pathology Division, National Cancer Center Research Institute;
  • 5Division of Gynecology, National Cancer Center Hospital, Tokyo, Japan;
  • 8Department of Obstetrics and Gynecology, Asahikawa Medical College, Asahikawa, Japan
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2007-08-01
Volume
67
Issue
15
Pages
7095-7105
ISSN
  • 0008-5472
  • 1538-7445
DOI
10.1158/0008-5472.can-06-4567
Cited by
68
References
4
Language
en

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