Identification of an ovarian clear cell carcinoma gene signature that reflects inherent disease biology and the carcinogenic processes
Identification of an ovarian clear cell carcinoma gene signature that reflects inherent disease biology and the carcinogenic processes
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DOI：
10.1038/onc.2009.470
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发表时间：
2010-03-01
期刊：
影响因子：
8
通讯作者：
Konishi, I.
中科院分区：
文献类型：
--
作者：
Yamaguchi, K.;Mandai, M.;Konishi, I.
卵巢透明细胞癌（OCCC）具有独特的临床特征，包括与子宫内膜异位症和预后不良的相关性。我们以前曾报道过，卵巢癌囊肿的内容物，特别是高浓度的游离铁，是通过铁诱导的持续氧化应激致癌的可能原因。在这项研究中，我们使用38个卵巢癌细胞系进行了基因表达微阵列分析，并确定了在OCCC细胞系和临床样本中通常表达的基因，这些基因包含OCCC基因签名。OCCC签名可重复地预测OCCC标本在其他微阵列数据集，这表明该基因谱反映了OCCC的固有生物学特性。OCCC签名包含已知的OCCC标记物，如肝细胞核因子-1 β（HNF-1 β）和多功能蛋白聚糖（VCAN），以及反映氧化应激的其他基因。OCCC签名基因的表达诱导永生化的卵巢表面上皮细胞与卵巢囊肿的内容物的处理，表明OCCC签名在很大程度上依赖于肿瘤微环境。OCCC特征基因的诱导至少部分是表观遗传学调控的，因为我们在OCCC细胞系中发现了HNF-1 β和VCAN的低甲基化。这项全基因组研究表明，肿瘤微环境诱导特定的基因表达谱，有助于不同癌症亚型的发展。Oncogene（2010）29，1741-1752; doi：10.1038/onc.2009.470; 2010年1月11日在线发表
Ovarian clear cell carcinoma (OCCC) shows unique clinical features including an association with endometriosis and poor prognosis. We previously reported that the contents of endometriotic cysts, especially high concentrations of free iron, are a possible cause of OCCC carcinogenesis through iron-induced persistent oxidative stress. In this study, we conducted gene expression microarray analysis using 38 ovarian cancer cell lines and identified genes commonly expressed in both OCCC cell lines and clinical samples, which comprise an OCCC gene signature. The OCCC signature reproducibly predicts OCCC specimens in other microarray data sets, suggesting that this gene profile reflects the inherent biological characteristics of OCCC. The OCCC signature contains known markers of OCCC, such as hepatocyte nuclear factor-1 beta (HNF-1 beta) and versican (VCAN), and other genes that reflect oxidative stress. Expression of OCCC signature genes was induced by treatment of immortalized ovarian surface epithelial cells with the contents of endometriotic cysts, indicating that the OCCC signature is largely dependent on the tumor microenvironment. Induction of OCCC signature genes is at least in part epigenetically regulated, as we found hypomethylation of HNF-1 beta and VCAN in OCCC cell lines. This genome-wide study indicates that the tumor microenvironment induces specific gene expression profiles that contribute to the development of distinct cancer subtypes. Oncogene (2010) 29, 1741-1752; doi:10.1038/onc.2009.470; published online 11 January 2010