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

Lin Zhang^a,b,c, Stefano Volinia^d, Tomas Bonome^e, George Adrian Calin^d, Joel Greshock^f,g, Nuo Yang^a, Chang-Gong Liu^d, Antonis Giannakakis^a,h, Pangiotis Alexiouⁱ, Kosei Hasegawa^a, Cameron N. Johnstone^j, Molly S. Megraw^k, Sarah Adams^a,b, Heini Lassus^l, Jia Huang^f, Sippy Kaur^l, Shun Liang^a, Praveen Sethupathy^k, Arto Leminen^l, Victor A. Simossisⁱ, Raphael Sandaltzopoulos^h, Yoshio Naomoto^m, Dionyssios Katsarosⁿ, Phyllis A. Gimotty^o, Angela DeMichele^j, Qihong Huang^p, Ralf Bützow^l, Anil K. Rustgi^j, Barbara L. Weber^f,g, Michael J. Birrer^e, Artemis G. Hatzigeorgiou^c,f,i,k, Carlo M. Croce^c,d, and George Coukos^a,b,c,f

^aCenter for Research on Early Detection and Cure of Ovarian Cancer and Gynecology, ^fAbramson Family Cancer Research Institute, and Departments of ^bObstetrics, ^jMedicine, ^kGenetics, and ^oBiostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA 19104; ^dDepartments of Molecular Virology, Immunology, and Medical Genetics, Ohio State University, Columbus, OH 43210; ^eCell and Cancer Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20814; ^hLaboratory of Gene Expression, Modern Diagnostic and Therapeutic Methods, Democritus University of Thrace, 68100 Alexandroupolis, Greece; ⁱInstitute of Molecular Oncology, Biomedical Sciences Research Center "Alexander Fleming", 166 72 Varkiza, Greece; ^lDepartment of Obstetrics and Gynecology, University of Helsinki, 00290, Helsinki, Finland; ^mDepartment of Surgical Oncology, Okayama University, Okayama 700-8530, Japan; ⁿDepartment of Obstetrics and Gynecology, University of Turin, 10124 Turin, Italy; and ^pThe Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104

Contributed by Carlo M. Croce, February 20, 2008 (sent for review December 15, 2007)

Abstract

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 15% and at least 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.

Dlk1-Gtl2 domain | noncoding RNA

Author contributions: S.V., T.B., G.A.C., J.G., N.Y., C.-G.L., A.G., and P.A. contributed equally to this work; L.Z., S.V., G.A.C., B.L.W., M.J.B., A.G.H., C.M.C., and G.C. designed research; T.B., J.G., N.Y., C.-G.L., A.G., P.A., K.H., C.N.J., M.S.M., S.A., H.L., J.H., S.K., S.L., P.S., A.L., V.A.S., and R.S. performed research; J.G., Y.N., D.K., P.A.G., A.D., Q.H., R.B., A.K.R., B.L.W., and A.G.H. contributed new reagents/analytic tools; L.Z., S.V., J.G., A.G.H., and G.C. analyzed data; and L.Z., A.G.H., C.M.C., and G.C. wrote the paper;.

^gPresent address: Translational Medicine and Genetics, GlaxoSmithKline, King of Prussia, PA 19406.

The authors declare no conflict of interest.

^cTo whom correspondence may be addressed. E-mail: linzhang{at}mail.med.upenn.edu, hatzigeorgiou{at}fleming.gr, carlo.croce{at}osumc.edu, or gcks{at}mail.med.upenn.edu

© 2008 by The National Academy of Sciences of the USA

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