An RNA interference lethality screen of the human druggable genome to identify molecular vulnerabilities in epithelial ovarian cancer.
An RNA interference lethality screen of the human druggable genome to identify molecular vulnerabilities in epithelial ovarian cancer.
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DOI：
10.1371/journal.pone.0047086
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Godwin AK
中科院分区：
文献类型：
--
作者：
Sethi G;Pathak HB;Zhang H;Zhou Y;Einarson MB;Vathipadiekal V;Gunewardena S;Birrer MJ;Godwin AK
靶向治疗已被用于对抗许多肿瘤类型;然而，很少有有效改善上皮性卵巢癌女性的总体生存率，乞求更好地了解这种致命的疾病，并确定可以有效靶向的肿瘤发生的基本驱动因素。因此，我们使用功能丧失筛查方法来帮助识别可能代表治疗干预关键点的分子脆弱性。我们采用了一种无偏的高通量致死性筛选，使用24，088 siRNA文库靶向6，000多个可药物化基因，并研究了它们对上皮性卵巢癌（EOC）细胞系生长和/或存活的影响。在另外的EOC细胞系和非致瘤性的人永生化卵巢上皮细胞系中重新筛选影响A1847细胞活力的前300个“命中”。发现53个候选基因在所有测试的致瘤细胞系中表现出效果。对这些命中的广泛验证将列表细化为四个高质量候选物（HSPA 5、NDC 80、NUF 2和PTN）。机制研究表明，沉默的三个基因导致细胞凋亡增加，而HSPA 5沉默似乎通过G1期细胞周期阻滞改变细胞生长。此外，两项独立的基因表达研究表明，NDC 80，NUF 2和PTN在浆液性腺癌中显著异常过表达。总的来说，我们的功能基因组学结果与基因组学数据相结合，为药物发现的前瞻性治疗靶点的确定提供了一个重要的无偏见的途径，这是卵巢癌的一个迫切和未满足的临床需求。
Targeted therapies have been used to combat many tumor types; however, few have effectively improved the overall survival in women with epithelial ovarian cancer, begging for a better understanding of this deadly disease and identification of essential drivers of tumorigenesis that can be targeted effectively. Therefore, we used a loss-of-function screening approach to help identify molecular vulnerabilities that may represent key points of therapeutic intervention. We employed an unbiased high-throughput lethality screen using a 24,088 siRNA library targeting over 6,000 druggable genes and studied their effects on growth and/or survival of epithelial ovarian cancer (EOC) cell lines. The top 300 “hits” affecting the viability of A1847 cells were rescreened across additional EOC cell lines and non-tumorigenic, human immortalized ovarian epithelial cell lines. Fifty-three gene candidates were found to exhibit effects in all tumorigenic cell lines tested. Extensive validation of these hits refined the list to four high quality candidates (HSPA5, NDC80, NUF2, and PTN). Mechanistic studies show that silencing of three genes leads to increased apoptosis, while HSPA5 silencing appears to alter cell growth through G1 cell cycle arrest. Furthermore, two independent gene expression studies show that NDC80, NUF2 and PTN were significantly aberrantly overexpressed in serous adenocarcinomas. Overall, our functional genomics results integrated with the genomics data provide an important unbiased avenue towards the identification of prospective therapeutic targets for drug discovery, which is an urgent and unmet clinical need for ovarian cancer.
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影响因子：
9.7
作者：
Cohen, Marie;Petignat, Patrick
通讯作者：
Petignat, Patrick
DOI：
10.1073/pnas.89.7.3070
发表时间：
1992-04-01
影响因子：
11.1
作者：
GODWIN, AK;MEISTER, A;ANDERSON, ME
通讯作者：
ANDERSON, ME
影响因子：
14.9
作者：
Gilsdorf, Moritz;Horn, Thomas;Boutros, Michael
通讯作者：
Boutros, Michael
DOI：
10.1007/978-1-61779-052-2_21
发表时间：
2011-01-01
期刊：
BIOMEDICAL NANOETECHNOLOGY: METHODS AND PROTOCOLS
影响因子：
--
作者：
Eifler, Aaron C.;Thaxton, C. Shad
通讯作者：
Thaxton, C. Shad
DOI：
10.1016/j.bbrc.2009.10.127
发表时间：
2009-12-25
影响因子：
3.1
作者：
Kaneko, Naoyuki;Miura, Koh;Horii, Akira
通讯作者：
Horii, Akira