Faculty Collaboration Database

Hypoxia-upregulated microRNA-630 targets Dicer, leading to increased tumor progression. Oncogene 2016 Aug 18;35(33):4312-20

Date

01/05/2016

Pubmed ID

26725326

Pubmed Central ID

PMC4931989

DOI

10.1038/onc.2015.492

Scopus ID

2-s2.0-84953238221 (requires institutional sign-in at Scopus site)   84 Citations

Abstract

MicroRNAs (miRNAs) are small RNA molecules that affect cellular processes by controlling gene expression. Recent studies have shown that hypoxia downregulates Drosha and Dicer, key enzymes in miRNA biogenesis, causing a decreased pool of miRNAs in cancer and resulting in increased tumor growth and metastasis. Here we demonstrate a previously unrecognized mechanism by which hypoxia downregulates Dicer. We found that miR-630, which is upregulated under hypoxic conditions, targets and downregulates Dicer expression. In an orthotopic mouse model of ovarian cancer, delivery of miR-630 using 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) nanoliposomes resulted in increased tumor growth and metastasis, and decreased Dicer expression. Treatment with the combination of anti-miR-630 and anti-vascular endothelial growth factor antibody in mice resulted in rescue of Dicer expression and significantly decreased tumor growth and metastasis. These results indicate that targeting miR-630 is a promising approach to overcome Dicer deregulation in cancer. As demonstrated in the study, use of DOPC nanoliposomes for anti-miR delivery serves as a better alternative approach to cell line-based overexpression of sense or antisense miRNAs, while avoiding potential in vitro selection effects. Findings from this study provide a new understanding of miRNA biogenesis downregulation observed under hypoxia and suggest therapeutic avenues to target this dysregulation in cancer.

Author List

Rupaimoole R, Ivan C, Yang D, Gharpure KM, Wu SY, Pecot CV, Previs RA, Nagaraja AS, Armaiz-Pena GN, McGuire M, Pradeep S, Mangala LS, Rodriguez-Aguayo C, Huang L, Bar-Eli M, Zhang W, Lopez-Berestein G, Calin GA, Sood AK

Author

Sunila Pradeep PhD Associate Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cell Hypoxia
Cell Line, Tumor
DEAD-box RNA Helicases
Disease Progression
Female
Gene Expression Regulation, Neoplastic
Humans
Liposomes
Mice
MicroRNAs
Neoplasms
Ovarian Neoplasms
Phosphatidylcholines
Ribonuclease III
Vascular Endothelial Growth Factor A