Epigenetic silencing of DKK2 and Wnt signal pathway components in human ovarian carcinoma
Epigenetic silencing of DKK2 and Wnt signal pathway components in human ovarian carcinoma
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人卵巢癌中 DKK2 和 Wnt 信号通路成分的表观遗传沉默
DOI：
10.1093/carcin/bgs278
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发表时间：
2012-12-01
期刊：
影响因子：
4.7
通讯作者：
Di, Wen
中科院分区：
文献类型：
--
作者：
Zhu, Jing;Zhang, Shu;Di, Wen
Wnt/-Catenin信号转导失调参与肿瘤发生。此外，Dickkopf（DKK）家族（DKK 1 DKK 4）的表观遗传修饰已被证明在Wnt信号传导调节中是重要的。本研究通过检测DKK 2在卵巢癌细胞系SKOV 3和ES-2中的表达和甲基化，以及78例卵巢癌患者组织（50例卵巢癌，20例良性肿瘤和8例正常卵巢组织）中的表达和甲基化，来评估Wnt拮抗剂DKK 2在上皮性卵巢癌（EOC）中的作用。DKK 2在EOC中高度下调;然而，DKK 2表达水平在正常组织和良性肿瘤中均较高。在大多数卵巢癌病例中，与良性肿瘤和正常卵巢组织中更常见的未甲基化形式相比，DKK 2是甲基化的。此外，在更高级别和阶段的EOC中，DKK 2可能通过甲基化而表观遗传学沉默。功能分析显示，DKK 2的过表达抑制SKOV 3和ES-2细胞系中的恶性细胞生长和侵袭。与模拟细胞相比，DKK 2转染细胞中Wnt信号下游基因的表达，包括β-catenin，c-Myc和cyclin D1，降低。基质金属蛋白酶-2和粘着斑激酶的表达也在DKK 2转染子中降低，支持表明细胞迁移和侵袭抑制的发现。本报告提供了新的迹象表明，DKK 2是一个独特的高甲基化的靶基因在EOC和DKK 2可能有助于肿瘤的发生在EOC通过Wnt/β-catenin信号传导机制。
Wnt/-Catenin signaling dysregulation is involved in tumorigenesis. Furthermore, epigenetic modification of the Dickkopf (DKK) family (DKK1DKK4) has been shown to be important in Wnt signaling regulation. In this study, the role of DKK2, a Wnt antagonist, in epithelial ovarian cancer (EOC) was evaluated by examining the expression and methylation of DKK2 in SKOV3 and ES-2 ovarian cancer cell lines and 78 tissues collected from patients (50 ovarian carcinoma, 20 benign tumor and 8 normal ovarian tissues). DKK2 is highly downregulated in EOCs; however, DKK2 expression levels are higher in both normal tissues and benign tumors. In most cases of ovarian carcinoma, DKK2 is methylated, compared with the more common unmethylated form present in benign tumors and normal ovarian tissues. Additionally, DKK2 may be epigenetically silenced by methylation in higher grades and stages of EOC. Functional analysis revealed that overexpression of DKK2 suppressed malignant cell growth and invasion in SKOV3 and ES-2 cell lines. The expression of the downstream genes of Wnt signaling, including -catenin, c-Myc and cyclin D1, was decreased in DKK2-transfected cells compared with mock cells. The expression of matrix metalloproteinase-2 and focal adhesion kinase were also decreased in DKK2 transfectants, supporting findings indicating inhibition of cell migration and invasion. This report provides novel indications that DKK2 is a unique hypermethylated target gene in EOC and that DKK2 may contribute to tumorigenesis in EOC through the Wnt/-catenin signaling mechanisms.