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[Cancer Research 66, 4627-4635, May 1, 2006]
© 2006 American Association for Cancer Research

Molecular Biology, Pathobiology, and Genetics

Integrative Genomic Analysis of Protein Kinase C (PKC) Family Identifies PKC{iota} as a Biomarker and Potential Oncogene in Ovarian Carcinoma

Lin Zhang1,3, Jia Huang2, Nuo Yang4, Shun Liang1, Andrea Barchetti1, Antonis Giannakakis1, Mark G. Cadungog1,3, Ann O'Brien-Jenkins1, Marco Massobrio7, Katherine F. Roby6, Dionyssios Katsaros7, Phyllis Gimotty5, Ralf Butzow8, Barbara L. Weber2 and George Coukos1,2,3

1 Center for Research on Reproduction and Women's Health, 2 Abramson Family Cancer Research Institute, Departments of 3 Obstetrics and Gynecology, 4 Genetics and Cell and Molecular Biology Program, and 5 Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; 6 Center for Reproductive Sciences, University of Kansas Medical Center, Kansas City, Kansas; 7 Department of Obstetrics and Gynecology, University of Turin, Turin, Italy; and 8 Departments of Obstetrics and Gynecology, University of Helsinki, Helsinki, Finland

Requests for reprints: George Coukos, Center for Research on Reproduction and Women's Health, University of Pennsylvania, 1331 Biomedical Research Building II/III, 421 Curie Boulevard, Philadelphia, PA 19104. Phone: 215-746-5137; Fax: 215-573-7627; E-mail: gcks{at}mail.med.upenn.edu.

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 PKC{iota} (43.8%), PKCß1 (37.1%), PKC{gamma} (27.6%), PKC{zeta} (22.5%), and PKC{theta} (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, PKC{iota} and PKC{theta}, were significantly up-regulated in ovarian cancer compared with normal ovary. Increased PKC{iota} expression correlated with tumor stage or grade, and PKC{iota} 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 PKC{iota} protein was also confirmed by tissue array and Western blot. Interestingly, overexpressed PKC{iota} did not affect ovarian cancer cell proliferation or apoptosis in vitro. However, decreased PKC{iota} expression significantly reduced anchorage-independent growth of ovarian cancer cells, whereas overexpression of PKC{iota} contributed to murine ovarian surface epithelium transformation in cooperation with mutant Ras. We propose that PKC{iota} may serve as an oncogene and a biomarker of aggressive disease in human ovarian cancer. (Cancer Res 2006; 66(9): 4627-35)




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