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Oncogene. 2016 Aug 18;35(33):4312-20. doi: 10.1038/onc.2015.492. Epub 2016 Jan 4.

Hypoxia-upregulated microRNA-630 targets Dicer, leading to increased tumor progression.

Author information

1
Department of Gynecologic Oncology and Reproductive Medicine, Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
2
Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
3
Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
4
Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
5
Department of Medicine, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
6
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
7
Department of Cancer Biology, Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
8
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

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.

PMID:
26725326
PMCID:
PMC4931989
DOI:
10.1038/onc.2015.492
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

of Potential Conflicts of Interest: No conflict of interests disclosed by authors.

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