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蛋白激酶C(PKC)家族的综合基因组分析确定PKCiota为卵巢癌的生物标志物和潜在致癌基因。

Integrative genomic analysis of protein kinase C (PKC) family identifies PKCiota as a biomarker and potential oncogene in ovarian carcinoma.

作者信息

Zhang Lin, Huang Jia, Yang Nuo, Liang Shun, Barchetti Andrea, Giannakakis Antonis, Cadungog Mark G, O'Brien-Jenkins Ann, Massobrio Marco, Roby Katherine F, Katsaros Dionyssios, Gimotty Phyllis, Butzow Ralf, Weber Barbara L, Coukos George

机构信息

Center for Research on Reproduction and Women's Health, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.

出版信息

Cancer Res. 2006 May 1;66(9):4627-35. doi: 10.1158/0008-5472.CAN-05-4527.

Abstract

The protein kinase C (PKC) family plays a key regulatory role in a wide range of cellular functions as well as in various cancer-associated signal transduction pathways. Here, we investigated the genomic alteration and gene expression of most known PKC family members in human ovarian cancer. The DNA copy number of PKC family genes was screened by a high-resolution array-based comparative genomic hybridization in 89 human ovarian cancer specimens. Five PKC genes exhibited significant DNA copy number gains, including PKCiota (43.8%), PKCbeta1 (37.1%), PKCgamma (27.6%), PKCzeta (22.5%), and PKCtheta (21.3%). None of the PKC genes exhibited copy number loss. The mRNA expression level of PKC genes was analyzed by microarray retrieval approach. Two of the amplified PKC genes, PKCiota and PKCtheta, were significantly up-regulated in ovarian cancer compared with normal ovary. Increased PKCiota expression correlated with tumor stage or grade, and PKCiota overexpression was seen mostly in ovarian carcinoma but not in other solid tumors. The above results were further validated by real-time reverse transcription-PCR with 54 ovarian cancer specimens and 24 cell lines; overexpression of PKCiota protein was also confirmed by tissue array and Western blot. Interestingly, overexpressed PKCiota did not affect ovarian cancer cell proliferation or apoptosis in vitro. However, decreased PKCiota expression significantly reduced anchorage-independent growth of ovarian cancer cells, whereas overexpression of PKCiota contributed to murine ovarian surface epithelium transformation in cooperation with mutant Ras. We propose that PKCiota may serve as an oncogene and a biomarker of aggressive disease in human ovarian cancer.

摘要

蛋白激酶C(PKC)家族在广泛的细胞功能以及各种癌症相关信号转导途径中发挥关键调节作用。在此,我们研究了人类卵巢癌中大多数已知PKC家族成员的基因组改变和基因表达。通过基于高分辨率阵列的比较基因组杂交技术,对89例人类卵巢癌标本中PKC家族基因的DNA拷贝数进行了筛查。5个PKC基因出现显著的DNA拷贝数增加,包括PKCiota(43.8%)、PKCbeta1(37.1%)、PKCgamma(27.6%)、PKCzeta(22.5%)和PKCtheta(21.3%)。没有PKC基因出现拷贝数丢失。通过微阵列检索方法分析了PKC基因的mRNA表达水平。与正常卵巢相比,两个扩增的PKC基因PKCiota和PKCtheta在卵巢癌中显著上调。PKCiota表达增加与肿瘤分期或分级相关,PKCiota过表达主要见于卵巢癌,而在其他实体瘤中未见。上述结果通过对54例卵巢癌标本和24个细胞系进行实时逆转录PCR进一步验证;组织芯片和蛋白质印迹也证实了PKCiota蛋白的过表达。有趣的是,过表达的PKCiota在体外不影响卵巢癌细胞的增殖或凋亡。然而,PKCiota表达降低显著降低了卵巢癌细胞的非锚定依赖性生长,而PKCiota的过表达与突变型Ras协同作用促进了小鼠卵巢表面上皮细胞转化。我们认为,PKCiota可能是人类卵巢癌中的一种癌基因和侵袭性疾病的生物标志物。

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