Matsumura Noriomi, Huang Zhiqing, Baba Tsukasa, Lee Paula S, Barnett Jason C, Mori Seiichi, Chang Jeffrey T, Kuo Wen-Lin, Gusberg Alison H, Whitaker Regina S, Gray Joe W, Fujii Shingo, Berchuck Andrew, Murphy Susan K
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC 27708, USA.
Mol Cancer Res. 2009 Feb;7(2):210-20. doi: 10.1158/1541-7786.MCR-08-0255. Epub 2009 Feb 10.
Survival of ovarian cancer patients is largely dictated by their response to chemotherapy, which depends on underlying molecular features of the malignancy. We previously identified YIN YANG 1 (YY1) as a gene whose expression is positively correlated with ovarian cancer survival. Herein, we investigated the mechanistic basis of this association. Epigenetic and genetic characteristics of YY1 in serous epithelial ovarian cancer were analyzed along with YY1 mRNA and protein. Patterns of gene expression in primary serous epithelial ovarian cancer and in the NCI60 database were investigated using computational methods. YY1 function and modulation of chemotherapeutic response in vitro was studied using small interfering RNA knockdown. Microarray analysis showed strong positive correlation between expression of YY1 and genes with YY1 and transcription factor E2F binding motifs in ovarian cancer and in the NCI60 cancer cell lines. Clustering of microarray data for these genes revealed that high YY1/E2F3 activity positively correlates with survival of patients treated with the microtubule-stabilizing drug paclitaxel. Increased sensitivity to taxanes, but not to DNA cross-linking platinum agents, was also characteristic of NCI60 cancer cell lines with a high YY1/E2F signature. YY1 knockdown in ovarian cancer cell lines results in inhibition of anchorage-independent growth, motility, and proliferation but also increases resistance to taxanes, with no effect on cisplatin sensitivity. These results, together with the prior demonstration of augmentation of microtubule-related genes by E2F3, suggest that enhanced taxane sensitivity in tumors with high YY1/E2F activity may be mediated by modulation of putative target genes with microtubule function.
卵巢癌患者的生存很大程度上取决于他们对化疗的反应，而这又取决于恶性肿瘤的潜在分子特征。我们之前鉴定出阴阳1（YY1）基因，其表达与卵巢癌患者的生存呈正相关。在此，我们研究了这种关联的机制基础。分析了浆液性上皮性卵巢癌中YY1的表观遗传和遗传特征，以及YY1的mRNA和蛋白质。使用计算方法研究了原发性浆液性上皮性卵巢癌和NCI60数据库中的基因表达模式。使用小干扰RNA敲低技术研究了YY1在体外的功能及其对化疗反应的调节作用。微阵列分析显示，在卵巢癌和NCI60癌细胞系中，YY1的表达与具有YY1和转录因子E2F结合基序的基因之间存在强正相关。对这些基因的微阵列数据进行聚类分析发现，高YY1/E2F3活性与接受微管稳定药物紫杉醇治疗的患者的生存呈正相关。对紫杉烷敏感性增加，但对DNA交联铂类药物不敏感，也是具有高YY1/E2F特征的NCI60癌细胞系的特点。在卵巢癌细胞系中敲低YY1会导致非锚定依赖性生长、迁移和增殖受到抑制，但也会增加对紫杉烷的耐药性，而对顺铂敏感性没有影响。这些结果，连同之前E2F3增强微管相关基因表达的证明，表明在具有高YY1/E2F活性的肿瘤中，增强的紫杉烷敏感性可能是通过调节具有微管功能的假定靶基因来介导的。
