Genomic and epigenetic alterations deregulate microRNA expression in human epithelial ovarian cancer.
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 approximately 15% and at least approximately 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.
Zhang
Lin
L
Center for Research on Early Detection and Cure of Ovarian Cancer and Gynecology, Department of Obstetrics, University of Pennsylvania, Philadelphia, PA 19104, USA. linzhang@mail.med.upenn.edu
Volinia
Stefano
S
Bonome
Tomas
T
Calin
George Adrian
GA
Greshock
Joel
J
Yang
Nuo
N
Liu
Chang-Gong
CG
Giannakakis
Antonis
A
Alexiou
Pangiotis
P
Hasegawa
Kosei
K
Johnstone
Cameron N
CN
Megraw
Molly S
MS
Adams
Sarah
S
Lassus
Heini
H
Huang
Jia
J
Kaur
Sippy
S
Liang
Shun
S
Sethupathy
Praveen
P
Leminen
Arto
A
Simossis
Victor A
VA
Sandaltzopoulos
Raphael
R
Naomoto
Yoshio
Y
Katsaros
Dionyssios
D
Gimotty
Phyllis A
PA
DeMichele
Angela
A
Huang
Qihong
Q
Bützow
Ralf
R
Rustgi
Anil K
AK
Weber
Barbara L
BL
Birrer
Michael J
MJ
Hatzigeorgiou
Artemis G
AG
Croce
Carlo M
CM
Coukos
George
G
D004273:DNA, Neoplasm; D015536:Down-Regulation / Q000235:genetics; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043244:Ribonuclease III / Q000235:genetics; D016019:Survival Analysis
D004273:DNA, Neoplasm; D035683:MicroRNAs; D012333:RNA, Messenger; C517918:DROSHA protein, human; D043244:Ribonuclease III