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Overexpression of S100A4 is associated with DNA hypomethylation and enhanced invasiveness in ovarian carcinomas

S100A4 的过度表达与卵巢癌 DNA 低甲基化和侵袭性增强相关

基本信息

批准号：
20591942
负责人：
KIKUCHI Norihiko
金额：
$ 3万
依托单位：
Shinshu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2008
资助国家：
日本
起止时间：
2008 至 2011
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20591942/
关键词：
卵巣癌脱メチル化 S100A4 S100A

项目摘要

The S100A4 protein which belongs to calcium binding S100 protein family has been suggested to be linked to metastatic phenotypes of cancer cell. In this study, we investigated the association between the expression of S100A4 and hypomethylation of the S100A4 first intron in ovarian carcinoma cells. We first used immunohistochemistry to examine the expression and localization of S100A4 in 113 epithelial ovarian neoplasms and analyzed its prognostic significance in patients with ovarian carcinoma. Ovarian carcinoma patients with strong nuclear S100A4 expression showed a significantly shorter survival than those without (p=0.0045). Three ovarian cancer cell lines (SKOV3, A2780, A2780/CDDP) expressed S100A4, however, OVCAR3 and OSEs did not. Matrigel invasion assay showed that the expression level of S100A4 was associated with invasive ability in ovarian cancer cells. The specific siRNA for S100A4 suppressed S100A4 expression and the invasiveness of A2780/CDDP cells. We then studied the relationship between DNA methylation status and S100A4 expression by bisulfite-modified DNA sequencing in ovarian cancer cell lines and 51 cases of ovarian carcinoma tissues. We found that CpG sites in the first intron of the S100A4 gene were hypomethylated in S100A4 positive ovarian carcinoma cells. In contrast, these CpG sites were methylated in S100A4 negative ovarian carcinoma cells and S100A4 expression was altered by 5-aza-2deoxycytidine treatment. In ovarian cancer tissues, 24 cases of S100A4 strongly positive were hypomethylated in the first intron of S100A4 gene and 14 of all S100A4 negative cases were methylated.

S100 A4蛋白属于钙结合S100蛋白家族，被认为与癌细胞的转移表型有关。在这项研究中，我们研究了卵巢癌细胞中S100 A4的表达与S100 A4第一内含子低甲基化之间的关系。我们首先使用免疫组织化学方法检测了113例卵巢上皮性肿瘤中S100 A4的表达和定位，并分析了其在卵巢癌患者预后中的意义。卵巢癌细胞核S100 A4强表达的患者生存期明显短于无表达的患者（p=0.0045）。3株卵巢癌细胞系（SKOV 3、A2780、A2780/CDDP）表达S100 A4，而OVCAR 3和OSEs不表达。Matrigel侵袭实验显示S100 A4的表达水平与卵巢癌细胞的侵袭能力相关。针对S100 A4的特异性siRNA抑制了S100 A4的表达和A2780/CDDP细胞的侵袭力。然后，我们研究了DNA甲基化状态和S100 A4表达的关系，通过亚硫酸氢盐修饰的DNA测序在卵巢癌细胞系和51例卵巢癌组织。我们发现S100 A4基因第一内含子的CpG位点在S100 A4阳性的卵巢癌细胞中是低甲基化的。相反，这些CpG位点在S100 A4阴性的卵巢癌细胞中被甲基化，并且S100 A4的表达被5-氮杂-2-脱氧胞苷处理改变。在卵巢癌组织中，24例S100 A4强阳性表达的卵巢癌组织中S100 A4基因第一内含子存在低甲基化，14例S100 A4阴性表达的卵巢癌组织中S100 A4基因第一内含子存在甲基化。