期刊
ONCOGENE
卷 35, 期 33, 页码 4312-4320出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2015.492
关键词
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资金
- National Institutes of Health [P30 CA016672, CA109298, UH2TR000943-01, P50 CA083639, P50 CA098258, CA128797, U54 CA151668, U24CA143835]
- Cancer Prevention and Research Institute of Texas [RP110595]
- Ovarian Cancer Research Fund, Inc. (Program Project Development Grant)
- Red and Charline McCombs Institute for the Early Detection and Treatment of Cancer
- RGK Foundation
- Gilder Foundation
- Blanton-Davis Ovarian Cancer Research Program
- Betty Anne Asche Murray Distinguished Professorship
- Russell and Diana Hawkins Family Foundation Discovery Fellowship
- Ovarian Cancer Research Fund, Inc.
- Foundation for Women's Cancer
- Cancer Prevention and Research Institute of Texas training grants [RP101502, RP101489]
- NCI-DHHS-NIH T32 training grant [T32 CA101642]
- NCI (T32 training grant) [CA009666]
- Conquer Cancer Foundation ASCO Young Investigator Award
- DoCM Advanced Scholar Program
- Research Training Award from Cancer Prevention and Research Institute of Texas (CPRIT) [RP140106]
- Altman Goldstein Discovery fellowship
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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