期刊
CANCER
卷 112, 期 7, 页码 1489-1502出版社
WILEY-BLACKWELL
DOI: 10.1002/cncr.23323
关键词
genomic imprinting; tumor suppressor gene; ARHI; PEG3; ovarian cancer
类别
资金
- NCI NIH HHS [CA80957, CA64602] Funding Source: Medline
BACKGROUND. Imprinted tumor suppressor genes may be particularly important in the pathogenesis of ovarian cancer. Two imprinted genes, paternally expressed 3 (PEG3) and aplasia Ras homologue member I (ARHI), are the most frequently down-regulated in ovarian cancers on gene expression arrays. METHODS. PEG3 and ARHI expression levels were evaluated with real-time reverse-transcriptase polymerase chain reaction (PCR) analysis. Promoter methylation was measured by pyrosequencing, and loss of heterozygosity (LOH) was detected by PCR-LOH assays. RESULTS. PEG3 was down-regulated in 75% and ARHI was down-regulated in 88% of 40 ovarian cancers. ARHI CpG islands I and II were hypermethylated in 13 of 42 ovarian cancers (31%) and in 5 of 42 ovarian cancers (12%), respectively, and hypermethylation was associated with reduced ARHI expression in all 18 samples of ovarian cancer with CpG island hypermethylation. PEG3 was hypermethylated in 11 of 42 ovarian cancers (26%), and PEG3 expression was down-regulated in 10 of those 11 cancers. LOH was detected in 8 of 35 informative cases for ARHI (23%) and in 5 of 25 informative cases for PEG3 (20%). PEG3 and ARHI expression was highly correlated in human ovarian cancers (correlation coefficient [R] = 0.69; P < .0001). PEG3 and ARHI also were methylated concordantly in ovarian cancers (11 = 0.36; P = .019). Re-expression of PEG3, similar to that of ARHI, markedly inhibited ovarian cancer growth. ARHI and PEG3 expression could be restored by treatment with 5-aza-2'-deoxycytidine and trichostatin A, consistent with the importance of promoter methylation and histone acetylation in regulating expression of both genes. CONCLUSIONS. Loss of expression of the growth-inhibitory imprinted genes ARHI and PEG3 through promoter methylation, LOH, and other mechanisms may stimulate clonogenic growth and contribute to the pathogenesis of a majority of ovarian cancers.
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