Zhang Lin, Huang Jia, Yang Nuo, Greshock Joel, Liang Shun, Hasegawa Kosei, Giannakakis Antonis, Poulos Nikolaos, O'Brien-Jenkins Ann, Katsaros Dionyssios, Butzow Ralf, Weber Barbara L, Coukos George
Center for Research on Early Detection and Cure of Ovarian Cancer, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Clin Cancer Res. 2007 Sep 15;13(18 Pt 1):5314-21. doi: 10.1158/1078-0432.CCR-06-2660.
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.
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.
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.
We propose that PIK3R3 may serve as a potential therapeutic target in human ovarian cancer.
磷脂酰肌醇3'-激酶（PI3K）家族在多种癌症相关信号转导通路中发挥关键调节作用。在此，我们研究了人类上皮性卵巢癌中大多数已知PI3K家族成员的基因组改变和基因表达。
通过高分辨率阵列比较基因组杂交技术，对89例人类卵巢癌标本中PI3K家族基因的DNA拷贝数进行筛选。采用微阵列检索方法分析PI3K基因的mRNA表达水平，并通过实时逆转录PCR进一步验证。在组织芯片上分析卵巢癌中p55γ蛋白的表达。使用小干扰RNA研究PIK3R3在卵巢癌中的功能。
在卵巢癌中，12个PI3K基因中有6个表现出显著的DNA拷贝数增加（>20%），包括PIK3CA（23.6%）、PIK3CB（27.0%）、PIK3CG（25.8%）、PIK3R2（29.2%）、PIK3R3（21.3%）和PIK3C2B（40.4%）。其中，与正常卵巢相比，只有PIK3R3在卵巢癌中的mRNA表达水平显著上调。在肝癌、前列腺癌和乳腺癌中也观察到PIK3R3 mRNA表达上调。卵巢癌细胞系（n = 18）中PIK3R3 mRNA表达水平显著高于人卵巢表面上皮细胞（n = 6，P = 0.002）。组织芯片分析证实卵巢癌中p55γ蛋白过表达。此外，我们发现通过小干扰RNA敲低PIK3R3表达可显著增加培养的卵巢癌细胞系中的细胞凋亡。
我们提出PIK3R3可能是人类卵巢癌的一个潜在治疗靶点。
