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

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 PKCt, (43.8%), PKC beta 1 (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, PKCt, and PKC theta, were significantly up-regulated in ovarian cancer compared with normal ovary. Increased PKCt expression correlated with tumor stage or grade, and PKCt 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 PKCt protein was also confirmed by tissue array and Western blot. Interestingly, overexpressed PKCt did not affect ovarian cancer cell proliferation or apoptosis in vitro. However, decreased PKCt expression significantly reduced anchorage-independent growth of ovarian cancer cells, whereas overexpression of PKCt contributed to marine ovarian surface epithelium transformation in cooperation with mutant Ras. We propose that PKCt may serve as an oncogene and a biomarker of aggressive disease in human ovarian cancer.