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Integrative Genomic Analysis of Phosphatidylinositol 3'-Kinase Family Identifies PIK3R3 as a Potential Therapeutic Target in Epithelial Ovarian Cancer

Authors' Affiliations: ¹ Center for Research on Early Detection and Cure of Ovarian Cancer, ² Department of Obstetrics and Gynecology, and ³ Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; ⁴ Department of Obstetrics and Gynecology, University of Turin, Turin, Italy; ⁵ Departments of Obstetrics and Gynecology, University of Helsinki, Helsinki, Finland; ⁶ Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; and ⁷ Laboratory of Gene Expression, Modern Diagnostic and Therapeutic Methods, Democritus University of Thrace, Alexandroupolis, Greece

Requests for reprints: Lin Zhang, University of Pennsylvania, Rm. 1209 BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104. Phone: 215-573-4780; Fax: 215-573-7627; E-mail: linzhang{at}mail.med.upenn.edu.

Purpose: The phosphatidylinositol 3'-kinase (PI3K) family plays a key regulatory role in various cancer-associated signal transduction pathways. Here, we investigated the genomic alterations and gene expression of most known PI3K family members in human epithelial ovarian cancer.

Experimental Design: The DNA copy number of PI3K family genes was screened by a high-resolution array comparative genomic hybridization in 89 human ovarian cancer specimens. The mRNA expression level of PI3K genes was analyzed by microarray retrieval approach, and further validated by real-time reverse transcription-PCR. The expression of p55 protein in ovarian cancer was analyzed on tissue arrays. Small interfering RNA was used to study the function of PIK3R3 in ovarian cancer.

Results: In ovarian cancer, 6 of 12 PI3K genes exhibited significant DNA copy number gains (>20%), including PIK3CA (23.6%), PIK3CB (27.0%), PIK3CG (25.8%), PIK3R2 (29.2%), PIK3R3 (21.3%), and PIK3C2B (40.4%). Among those, only PIK3R3 had significantly up-regulated mRNA expression level in ovarian cancer compared with normal ovary. Up-regulated PIK3R3 mRNA expression was also observed in liver, prostate, and breast cancers. The PIK3R3 mRNA expression level was significantly higher in ovarian cancer cell lines (n = 18) than in human ovarian surface epithelial cells (n = 6, P = 0.002). Overexpression of p55 protein in ovarian cancer was confirmed by tissue array analysis. In addition, we found that knockdown of PIK3R3 expression by small interfering RNA significantly increased the apoptosis in cultured ovarian cancer cell lines.

Conclusion: We propose that PIK3R3 may serve as a potential therapeutic target in human ovarian cancer.

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