Integrative genomic analysis of protein kinase C (PKC) family identifies PKCiota 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 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.
Zhang
Lin
L
Center for Research on Reproduction and Women's Health, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Huang
Jia
J
Yang
Nuo
N
Liang
Shun
S
Barchetti
Andrea
A
Giannakakis
Antonis
A
Cadungog
Mark G
MG
O'Brien-Jenkins
Ann
A
Massobrio
Marco
M
Roby
Katherine F
KF
Katsaros
Dionyssios
D
Gimotty
Phyllis
P
Butzow
Ralf
R
Weber
Barbara L
BL
Coukos
George
G
D014408:Biomarkers, Tumor / Q000235:genetics*; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D005260:Female; D018628:Gene Dosage; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics*; D009154:Mutation; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics*; D011493:Protein Kinase C / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation; D018631:ras Proteins / Q000235:genetics; D000099293:Protein Kinase C-lambda
D014408:Biomarkers, Tumor; D002945:Cisplatin; D007527:Isoenzymes; D011493:Protein Kinase C; D012333:RNA, Messenger; D018631:ras Proteins; D000099293:Protein Kinase C-lambda