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Frequent inactivation of a putative tumor suppressor, angiopoietin-like protein 2, in ovarian cancer.
Cancer Res. 2008 Jul 01; 68(13):5067-75.CR

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.

Authors+Show Affiliations

Department of Molecular Cytogenetics, Medical Research Institute and School of Biomedical Science, Tokyo Medical and Dental University, Tokyo, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18593905

Citation

Kikuchi, Ryoko, et al. "Frequent Inactivation of a Putative Tumor Suppressor, Angiopoietin-like Protein 2, in Ovarian Cancer." Cancer Research, vol. 68, no. 13, 2008, pp. 5067-75.
Kikuchi R, Tsuda H, Kozaki K, et al. Frequent inactivation of a putative tumor suppressor, angiopoietin-like protein 2, in ovarian cancer. Cancer Res. 2008;68(13):5067-75.
Kikuchi, R., Tsuda, H., Kozaki, K., 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, 68(13), 5067-75. https://doi.org/10.1158/0008-5472.CAN-08-0062
Kikuchi R, et al. Frequent Inactivation of a Putative Tumor Suppressor, Angiopoietin-like Protein 2, in Ovarian Cancer. Cancer Res. 2008 Jul 1;68(13):5067-75. PubMed PMID: 18593905.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Frequent inactivation of a putative tumor suppressor, angiopoietin-like protein 2, in ovarian cancer. AU - Kikuchi,Ryoko, AU - Tsuda,Hitoshi, AU - Kozaki,Ken-ichi, AU - Kanai,Yae, AU - Kasamatsu,Takahiro, AU - Sengoku,Kazuo, AU - Hirohashi,Setsuo, AU - Inazawa,Johji, AU - Imoto,Issei, PY - 2008/7/3/pubmed PY - 2008/8/6/medline PY - 2008/7/3/entrez SP - 5067 EP - 75 JF - Cancer research JO - Cancer Res VL - 68 IS - 13 N2 - 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. SN - 1538-7445 UR - https://www.unboundmedicine.com/medline/citation/18593905/Frequent_inactivation_of_a_putative_tumor_suppressor_angiopoietin_like_protein_2_in_ovarian_cancer_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=18593905 DB - PRIME DP - Unbound Medicine ER -