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Genomic and epigenetic alterations deregulate microRNA expression in human epithelial ovarian cancer

Zhang, Lin, Volinia, Stefano, Bonome, Tomas, Calin, George Adrian, Greshock, Joel, Yang, Nuo, Liu, Chang-Gong, Giannakakis, Antonis, Alexiou, Pangiotis, Hasegawa, Kosei, Johnstone, Cameron N., Megraw, Molly S., Adams, Sarah, Lassus, Heini, Huang, Jia, Kaur, Sippy, Liang, Shun, Sethupathy, Praveen, Leminen, Arto, Simossis, Victor A., Sandaltzopoulos, Raphael, Naomoto, Yoshio, Katsaros, Dionyssios, Gimotty, Phyllis A., DeMichele, Angela, Huang, Qihong, Bützow, Ralf, Rustgi, Anil K., Weber, Barbara L., Birrer, Michael J., Hatzigeorgiou, Artemis G., Croce, Carlo M., Coukos, George
Proceedings of the National Academy of Sciences of the United States of America 2008 v.105 no.19 pp. 7004-7009
animal ovaries, biomarkers, chromosomes, comparative genomic hybridization, complementary DNA, epigenetics, gene expression regulation, genomics, humans, microRNA, microarray technology, non-coding RNA, ovarian neoplasms, transcription (genetics), tumor suppressor genes
MicroRNAs (miRNAs) are an abundant class of small noncoding RNAs that function as negative gene regulators. miRNA deregulation is involved in the initiation and progression of human cancer; however, the underlying mechanism and its contributions to genome-wide transcriptional changes in cancer are still largely unknown. We studied miRNA deregulation in human epithelial ovarian cancer by integrative genomic approach, including miRNA microarray (n = 106), array-based comparative genomic hybridization (n = 109), cDNA microarray (n = 76), and tissue array (n = 504). miRNA expression is markedly down-regulated in malignant transformation and tumor progression. Genomic copy number loss and epigenetic silencing, respectively, may account for the down-regulation of [almost equal to]15% and at least [almost equal to]36% of miRNAs in advanced ovarian tumors and miRNA down-regulation contributes to a genome-wide transcriptional deregulation. Last, eight miRNAs located in the chromosome 14 miRNA cluster (Dlk1-Gtl2 domain) were identified as potential tumor suppressor genes. Therefore, our results suggest that miRNAs may offer new biomarkers and therapeutic targets in epithelial ovarian cancer.