Details

Autor(en) / Beteiligte

• Rupaimoole, R
• Ivan, C
• Yang, D
• Gharpure, K M
• Wu, S Y
• Pecot, C V
• Previs, R A
• Nagaraja, A S
• Armaiz-Pena, G N
• McGuire, M
• Pradeep, S
• Mangala, L S
• Rodriguez-Aguayo, C
• Huang, L
• Bar-Eli, M
• Zhang, W
• Lopez-Berestein, G
• Calin, G A
• Sood, A K

Titel

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

Ist Teil von

• Oncogene, 2016-08, Vol.35 (33), p.4312-4320

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2016

Link zum Volltext

Quelle

Electronic Journals Library

Beschreibungen/Notizen

• 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.