Integrative genomic analysis of protein kinase C (PKC) family identifies PKCiota as a biomarker and potential oncogene in ovarian carcinoma.
Integrative genomic analysis of protein kinase C (PKC) family identifies PKCiota as a biomarker and potential oncogene in ovarian carcinoma.
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DOI：
10.1158/0008-5472.can-05-4527
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发表时间：
2006-05
期刊：
影响因子：
11.2
通讯作者：
Lin Zhang;Jia Huang;N. Yang;Shun Liang;A. Barchetti;Antonis Giannakakis;Mark G. Cadungog;A. O’Brien-Jenkins;M. Massobrio;K. Roby;D. Katsaros;P. Gimotty;R. Butzow;B. Weber;G. Coukos
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文献类型：
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作者：
Lin Zhang;Jia Huang;N. Yang;Shun Liang;A. Barchetti;Antonis Giannakakis;Mark G. Cadungog;A. O’Brien-Jenkins;M. Massobrio;K. Roby;D. Katsaros;P. Gimotty;R. Butzow;B. Weber;G. Coukos
蛋白激酶C(PKC)家族在广泛的细胞功能以及各种癌症相关的信号转导途径中发挥着关键的调节作用。在这里，我们研究了大多数已知的PKC家族成员在卵巢癌中的基因组改变和基因表达。采用基于高分辨率阵列的比较基因组杂交法对89例卵巢癌组织中PKC家族基因的DNA拷贝数进行筛选。5个PKC基因的DNA拷贝数显著增加，包括PKCiota(43.8%)、PKCbeta1(37.1%)、PKCGamma(27.6%)、PKcheeta(22.5%)和PKCtheta(21.3%)。所有PKC基因均未出现拷贝数丢失。采用基因芯片检索技术分析PKC基因的表达水平。其中两个扩增的PKC基因PKCiota和PKCtheta在卵巢癌组织中的表达显著高于正常卵巢组织。PKCiota的高表达与肿瘤的分期或分级有关，PKCiota的过度表达主要见于卵巢癌，而在其他实体瘤中则不表达。用54例卵巢癌标本和24株卵巢癌细胞株进行实时荧光定量逆转录-聚合酶链式反应进一步验证了上述结果；组织芯片和Western印迹结果也证实了PKCiota蛋白的过表达。有趣的是，过表达的PKCiota在体外并不影响卵巢癌细胞的增殖或凋亡。然而，PKCiota的低表达显著降低了卵巢癌细胞的贴壁非依赖性生长，而PKCiota的高表达与突变型RAS协同作用促进了小鼠卵巢表面上皮细胞的转化。我们认为PKCiota可能是卵巢癌的癌基因和侵袭性疾病的生物标志物。
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.