Integrative genomic analysis of phosphatidylinositol 3'-kinase family identifies PIK3R3 as a potential therapeutic target in epithelial ovarian cancer.
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.
Zhang
Lin
L
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
Huang
Jia
J
Yang
Nuo
N
Greshock
Joel
J
Liang
Shun
S
Hasegawa
Kosei
K
Giannakakis
Antonis
A
Poulos
Nikolaos
N
O'Brien-Jenkins
Ann
A
Katsaros
Dionyssios
D
Butzow
Ralf
R
Weber
Barbara L
BL
Coukos
George
G
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
D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger; C523442:PIK3R3 protein, human