Notch3 gene amplification in ovarian cancer
Notch3 gene amplification in ovarian cancer
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DOI：
10.1158/0008-5472.can-05-3610
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发表时间：
2006-06-15
期刊：
影响因子：
11.2
通讯作者：
Wang, Tian-Li
中科院分区：
文献类型：
--
作者：
Park, Joon T.;Li, Mei;Wang, Tian-Li
基因扩增是激活癌基因的常见机制之一。在这项研究中，我们使用单核苷酸多态性阵列分析了31例高级别卵巢浆液性癌（女性最致命的妇科肿瘤性疾病）的全基因组DNA拷贝数变化。我们在31例卵巢高级别浆液性癌中的6例（19.5%）中发现了19p13.12的扩增子。该扩增通过数字核型分析、实时定量PCR和双色荧光原位杂交（FISH）分析进行验证。最小扩增子内所有34个基因的综合mRNA表达分析鉴定Notch 3为与非扩增肿瘤相比在扩增肿瘤中显示最显著过表达的基因。此外，Notch 3 DNA拷贝数与Notch 3蛋白表达正相关，基于平行的免疫组织化学和FISH研究在111个高级别肿瘤。通过γ-分泌酶抑制剂和Notch 3特异性小干扰RNA灭活Notch 3抑制过表达Notch 3的细胞系中的细胞增殖并诱导凋亡，但在具有最小量的Notch 3表达的细胞系中不抑制细胞增殖并诱导凋亡。这些结果表明，Notch 3扩增肿瘤的增殖和存活需要Notch 3，并且Notch 3的失活可以是卵巢癌的潜在治疗方法。
Gene amplification is one of the common mechanisms that activate oncogenes. In this study, we used single nucleotide polymorphism array to analyze genome-wide DNA copy number alterations in 31 high-grade ovarian serous carcinomas, the most lethal gynecologic neoplastic disease in women. We identified an amplicon at 19p13.12 in 6 of 31 (19.5%) ovarian high-grade serous carcinomas. This amplification was validated by digital karyotyping, quantitative real-time PCR, and dual-color fluorescence in situ hybridization (FISH) analysis. Comprehensive mRNA expression analysis of all 34 genes within the minimal amplicon identified Notch3 as the gene that showed most significant overexpression in amplified tumors compared with nonamplified tumors. Furthermore, Notch3 DNA copy number is positively correlated with Notch3 protein expression based on parallel immunohistochemistry and FISH studies in 111 high-grade tumors. Inactivation of Notch3 by both gamma-secretase inhibitor and Notch3-specific small interfering RNA suppressed cell proliferation and induced apoptosis in the cell lines that overexpressed Notch3 but not in those with minimal amount of Notch3 expression. These results indicate that Notch3 is required for proliferation and survival of Notch3-amplified tumors and inactivation of Notch3 can be a potential therapeutic approach for ovarian carcinomas.