Abstract
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-1beta (HNF-1beta) 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-1beta 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.
Highlights
Ovarian cancer is the fifth most common form of cancer in women (Bonome et al, 2008), and it has the worstWe previously reported that the contents of endometriotic cysts, especially the high concentration of free iron in these cysts, promote carcinogenesis through ironinduced persistent oxidative stress (Yamaguchi et al, 2008)
We showed that ovarian clear cell carcinoma (OCCC) cells can survive under conditions of high oxidative stress, suggesting that the cells encountering persistent oxidative stress in vivo in the unique environment of the endometriotic cyst may acquire such characteristics potentially leading to carcinogenesis
In the GSE6008 data set, 5667 U133A microarray probe sets were selected as differentially expressed between OCCC and non-OCCC tumors using significance analysis of microarrays (SAM) with a 5% false discovery rate q-value threshold (Figure 1a)
Summary
We previously reported that the contents of endometriotic cysts, especially the high concentration of free iron in these cysts, promote carcinogenesis through ironinduced persistent oxidative stress (Yamaguchi et al, 2008). Our report was the first to show a relationship between iron and ovarian cancer development in endometriosis. Microarray analysis of tumor samples is a powerful tool for the development of profiles that can distinguish, identify and classify discrete subsets of disease and predict disease outcome or the response to therapy in Ovarian clear cell carcinoma signature and carcinogenesis K Yamaguchi et al various cancers, such as breast, bladder, lung, colon or hematopoietic malignancies (Ito et al, 2007; GarciaEscudero and Paramio, 2008). Several studies have reported genes that are differentially expressed in OCCC. There was little overlap among the genes identified in these studies, and a reproducible gene signature specific for OCCC has not yet been identified (Schwartz et al, 2002; Schaner et al, 2003; Tsuchiya et al, 2003; Marquez et al, 2005; Zorn et al, 2005)
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