Feng Weiwei, Marquez Rebecca T, Lu Zhen, Liu Jinsong, Lu Karen H, Issa Jean-Pierre J, Fishman David M, Yu Yinhua, Bast Robert C
Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4009, USA.
Cancer. 2008 Apr 1;112(7):1489-502. doi: 10.1002/cncr.23323.
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.
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.
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 (R=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.
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.
印记肿瘤抑制基因在卵巢癌的发病机制中可能尤为重要。两个印记基因，父源表达基因3（PEG3）和Ras同源结构域家族成员I（ARHI），在基因表达阵列上是卵巢癌中最常下调的基因。
采用实时逆转录聚合酶链反应（PCR）分析评估PEG3和ARHI的表达水平。通过焦磷酸测序检测启动子甲基化，通过PCR-LOH分析检测杂合性缺失（LOH）。
在40例卵巢癌中，75%的病例PEG3下调，88%的病例ARHI下调。42例卵巢癌中有13例（31%）的ARHI CpG岛I发生高甲基化，42例中有5例（12%）的ARHI CpG岛II发生高甲基化，在所有18例发生CpG岛高甲基化的卵巢癌样本中，高甲基化均与ARHI表达降低相关。42例卵巢癌中有11例（26%）的PEG3发生高甲基化，在这11例癌症中有10例PEG3表达下调。在35例有信息的病例中，8例（23%）检测到ARHI的LOH，在25例有信息的病例中，5例（20%）检测到PEG3的LOH。在人类卵巢癌中，PEG3和ARHI的表达高度相关（相关系数[R]=0.69；P<0.0001）。在卵巢癌中，PEG3和ARHI也存在一致的甲基化（R=0.36；P=0.019）。与ARHI相似，PEG3的重新表达显著抑制卵巢癌生长。用5-氮杂-2'-脱氧胞苷和曲古抑菌素A处理可恢复ARHI和PEG3的表达，这与启动子甲基化和组蛋白乙酰化在调节这两个基因表达中的重要性一致。
生长抑制性印记基因ARHI和PEG3通过启动子甲基化、LOH及其他机制导致的表达缺失可能会刺激克隆性生长，并在大多数卵巢癌的发病机制中发挥作用。
