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.
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Acknowledgements
Portions of this work were supported by the National Institutes of Health (P30 CA016672, CA109298, UH2TR000943-01, P50 CA083639, P50 CA098258, CA128797, U54 CA151668 and U24CA143835); the Cancer Prevention and Research Institute of Texas (RP110595); the Ovarian Cancer Research Fund, Inc. (Program Project Development Grant); the Red and Charline McCombs Institute for the Early Detection and Treatment of Cancer; the RGK Foundation; the Gilder Foundation; the Blanton-Davis Ovarian Cancer Research Program; and the Betty Anne Asche Murray Distinguished Professorship (AKS). RR is supported in part by the Russell and Diana Hawkins Family Foundation Discovery Fellowship. S.Y.W. is supported by the Ovarian Cancer Research Fund, Inc., Foundation for Women’s Cancer and Cancer Prevention and Research Institute of Texas training grants (RP101502 and RP101489). RAP is supported by the NCI-DHHS-NIH T32 training grant (T32 CA101642). CVP is supported by a grant from the NCI (T32 training grant CA009666), the 2011 Conquer Cancer Foundation ASCO Young Investigator Award and the DoCM Advanced Scholar Program. ASN is supported by a Research Training Award from the Cancer Prevention and Research Institute of Texas (CPRIT RP140106). KMG is supported by Altman Goldstein Discovery fellowship. We thank Dr Xinna Zhang for assistance with the in situ hybridization analysis.
Author contributions
Conception and design, development of methodology, writing, review and/or revision of the manuscript, administrative, technical or material support (that is, reporting or organizing data, constructing databases) and study supervision: RR and AKS. Acquisition of data (provided animals, acquired and managed patients, provided facilities and so on): RR, SYW, CVP, RAP, KMG, ASN, GNA-P, MMcG, SP, LSM, CR-A, LH, MB-E, WZ, GL-B, GAC and AKS. Analysis and interpretation of data (for example, statistical analysis, biostatistics and computational analysis): CI and DY.
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Rupaimoole, R., Ivan, C., Yang, D. et al. Hypoxia-upregulated microRNA-630 targets Dicer, leading to increased tumor progression. Oncogene 35, 4312–4320 (2016). https://doi.org/10.1038/onc.2015.492
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DOI: https://doi.org/10.1038/onc.2015.492
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