Frequent inactivation of a putative tumor suppressor, angiopoietin-like protein 2, in ovarian cancer
Frequent inactivation of a putative tumor suppressor, angiopoietin-like protein 2, in ovarian cancer
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DOI：
10.1158/0008-5472.can-08-0062
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发表时间：
2008-07-01
期刊：
影响因子：
11.2
通讯作者：
Imoto, Issei
中科院分区：
文献类型：
--
作者：
Kikuchi, Ryoko;Tsuda, Hitoshi;Imoto, Issei
血管生成素样蛋白2（Angiopoietin-like protein 2，ANGPTL 2）是属于血管生成素家族的一种分泌性蛋白，其成员参与各种生物学过程，尽管其受体仍然未知。我们在使用基于内部阵列的比较基因组杂交筛选一组卵巢癌（OC）细胞系的基因组拷贝数畸变的过程中鉴定了ANGPTL 2（9q33.3）的纯合丢失。在正常卵巢组织和永生化的正常卵巢上皮细胞中观察到ANGPTL 2 mRNA表达，但在一些没有其纯合缺失的OC系（23个系中的18个）中降低，并且在5-氮杂2 '-脱氧胞苷处理后恢复。具有明确启动子活性的ANGPTL 2 CpG岛周围序列的甲基化状态与表达呈负相关。ANGPTL 2甲基化在原发性OC组织中也经常观察到。在原发性OC的免疫组织化学分析中，ANGPTL 2表达经常降低（100例中有51例），并与甲基化状态呈负相关。显示ANGPTL 2免疫反应性降低的OC患者在早期阶段（I期和II期）的生存率显著较差，但在晚期阶段（III期和IV期）的生存率较好。ANGPTL 2表达的恢复或用含有ANGPTL 2的条件培养基处理抑制了最初缺乏该基因表达的OC细胞的生长，而内源性ANGPTL 2的敲除加速了具有ANGPTL 2表达的OC细胞的生长。这些结果表明，至少部分地，通过ANGPTL 2启动子的超甲基化引起的表观遗传沉默导致ANGPTL 2功能的丧失，这可能是OC以阶段依赖性方式致癌的一个因素。
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.