miR-210 links hypoxia with cell cycle regulation and is deleted in human epithelial ovarian cancer.
Tumor growth results in hypoxia. Understanding the mechanisms of gene expression reprogramming under hypoxia may provide important clues to cancer pathogenesis. We studied miRNA genes that are regulated by hypoxia in ovarian cancer cell lines by TaqMan miRNA assay containing 157 mature miRNAs. MiR-210 was the most prominent miRNA consistently stimulated under hypoxic conditions. We provide evidence for the involvement of the HIF signaling pathway in miR-210 regulation. Biocomputational analysis and in vitro assays demonstrated that e2f transcription factor 3 (e2f3), a key protein in cell cycle, is regulated by miR-210. E2F3 was further confirmed to be downregulated at the protein level upon induction of miR-210. Importantly, we found remarkably high frequency of miR-210 gene copy deletions in ovarian cancer patients (64%, n = 114) and that gene copy number correlates with miR-210 expression levels. Taken together, our results indicate that miR-210 plays a crucial role in tumor onset as a key regulator of the hypoxia response and provide evidence for a link between hypoxia and the regulation of cell cycle.
Center for Research on Early Detection and Cure of Ovarian Cancer, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Antonis
A
Giannakakis
Raphael
R
Sandaltzopoulos
Joel
J
Greshock
Shun
S
Liang
Jia
J
Huang
Kosei
K
Hasegawa
Chunsheng
C
Li
Ann
A
O'Brien-Jenkins
Dionyssios
D
Katsaros
Barbara L
BL
Weber
Celeste
C
Simon
George
G
Coukos
Lin
L
Zhang
D002453:Cell Cycle / Q000502:physiology*; D045744:Cell Line, Tumor; D019295:Computational Biology / Q000379:methods; D005260:Female; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017384:Sequence Deletion
C524940:MIRN21 microRNA, human; D035683:MicroRNAs