title: Integrative genomic analysis of phosphatidylinositol 3'-kinase family identifies PIK3R3 as a potential therapeutic target in epithelial ovarian cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 p55gamma 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 p55gamma 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.
  
  
  CONCLUSIONS
  We propose that PIK3R3 may serve as a potential therapeutic target in human ovarian cancer.
authors: Center for Research on Early Detection and Cure of Ovarian Cancer, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. linzhang@mail.med.upenn.edu
authors: Lin
authors: L
authors: Zhang
authors: Jia
authors: J
authors: Huang
authors: Nuo
authors: N
authors: Yang
authors: Joel
authors: J
authors: Greshock
authors: Shun
authors: S
authors: Liang
authors: Kosei
authors: K
authors: Hasegawa
authors: Antonis
authors: A
authors: Giannakakis
authors: Nikolaos
authors: N
authors: Poulos
authors: Ann
authors: A
authors: O'Brien-Jenkins
authors: Dionyssios
authors: D
authors: Katsaros
authors: Ralf
authors: R
authors: Butzow
authors: Barbara L
authors: BL
authors: Weber
authors: George
authors: G
authors: Coukos
mesh_terms: D002277:Carcinoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D023281:Genomics; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000032:analysis / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger; C523442:PIK3R3 protein, human