An RNA interference lethality screen of the human druggable genome to identify molecular vulnerabilities in epithelial ovarian cancer.

Authors:
Geetika Sethi
Geetika Sethi
University of Kansas Medical Center
United States
Harsh B Pathak
Harsh B Pathak
University of Kansas Medical Center
Hong Zhang
Hong Zhang
Peking University First Hospital
China
Yan Zhou
Yan Zhou
Fox Chase Cancer Center
China
Margret B Einarson
Margret B Einarson
Institute for Cancer Research
United States
Vinod Vathipadiekal
Vinod Vathipadiekal
National Chemical Laboratory
Philadelphia | United States
Sumedha Gunewardena
Sumedha Gunewardena
University of Kansas Medical Center
United States
Michael J Birrer
Michael J Birrer
Massachusetts General Hospital
Boston | United States

PLoS One 2012 9;7(10):e47086. Epub 2012 Oct 9.

Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, United States of America.

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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Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0047086PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3467214PMC

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May 2013
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