Frequent inactivation of a putative tumor suppressor, angiopoietin-like protein 2, in ovarian cancer

Ryoko Kikuchi, Hitoshi Tsuda, Ken Ichi Kozaki, Yae Kanai, Takahiro Kasamatsu, Kazuo Sengoku, Setsuo Hirohashi, Johji Inazawa, Issei Imoto

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Angiopoietin-like protein 2 (ANGPTL2) is a secreted protein belonging to the angiopoietin family, the members of which are implicated in various biological processes, although its receptor remains unknown. We identified a homozygous loss of ANGPTL2 (9q33.3) in the course of screening a panel of ovarian cancer (OC) cell lines for genomic copy-number aberrations using in-house array-based comparative genomic hybridization. ANGPTL2 mRNA expression was observed in normal ovarian tissue and immortalized normal ovarian epithelial cells, but was reduced in some OC lines without its homozygous deletion (18 of 23 lines) and restored after treatment with 5-aza 2′-deoxycytidine. The methylation status of sequences around the ANGPTL2 CpG-island with clear promoter activity inversely correlated with expression. ANGPTL2 methylation was frequently observed in primary OC tissues as well. In an immunohistochemical analysis of primary OCs, ANGPTL2 expression was frequently reduced (51 of 100 cases), and inversely correlated with methylation status. Patients with OC showing reduced ANGPTL2 immunoreactivity had significantly worse survival in the earlier stages (stages I and II), but better survival in advanced stages (stages III and IV). The restoration of ANGPTL2 expression or treatment with conditioned medium containing ANGPTL2 inhibited the growth of OC cells originally lacking the expression of this gene, whereas the knockdown of endogenous ANGPTL2 accelerated the growth of OC cells with the expression of ANGPTL2. These results suggest that, at least partly, epigenetic silencing by hypermethylation of the ANGPTL2 promoter leads to a loss of ANGPTL2 function, which may be a factor in the carcinogenesis of OC in a stage-dependent manner.

Original languageEnglish
Pages (from-to)5067-5075
Number of pages9
JournalCancer Research
Volume68
Issue number13
DOIs
Publication statusPublished - 2008 Jul 1
Externally publishedYes

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Angiopoietins
Ovarian Neoplasms
Neoplasms
Proteins
Methylation
decitabine
Gene Knockdown Techniques
Biological Phenomena
CpG Islands
Comparative Genomic Hybridization
Survival
Conditioned Culture Medium
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Frequent inactivation of a putative tumor suppressor, angiopoietin-like protein 2, in ovarian cancer. / Kikuchi, Ryoko; Tsuda, Hitoshi; Kozaki, Ken Ichi; Kanai, Yae; Kasamatsu, Takahiro; Sengoku, Kazuo; Hirohashi, Setsuo; Inazawa, Johji; Imoto, Issei.

In: Cancer Research, Vol. 68, No. 13, 01.07.2008, p. 5067-5075.

Research output: Contribution to journalArticle

Kikuchi, R, Tsuda, H, Kozaki, KI, Kanai, Y, Kasamatsu, T, Sengoku, K, Hirohashi, S, Inazawa, J & Imoto, I 2008, 'Frequent inactivation of a putative tumor suppressor, angiopoietin-like protein 2, in ovarian cancer', Cancer Research, vol. 68, no. 13, pp. 5067-5075. https://doi.org/10.1158/0008-5472.CAN-08-0062
Kikuchi, Ryoko ; Tsuda, Hitoshi ; Kozaki, Ken Ichi ; Kanai, Yae ; Kasamatsu, Takahiro ; Sengoku, Kazuo ; Hirohashi, Setsuo ; Inazawa, Johji ; Imoto, Issei. / Frequent inactivation of a putative tumor suppressor, angiopoietin-like protein 2, in ovarian cancer. In: Cancer Research. 2008 ; Vol. 68, No. 13. pp. 5067-5075.
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AU - Sengoku, Kazuo

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