title: Hypoxia-upregulated microRNA-630 targets Dicer, leading to increased tumor progression.
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.
authors.affiliation: 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.|Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: R
authors.initials: R
authors.lastname: Rupaimoole
authors.affiliation: 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.|Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: C
authors.identifier: 0000-0002-4848-0168
authors.initials: C
authors.lastname: Ivan
authors.affiliation: Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Yang
authors.affiliation: 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.|Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Gharpure
authors.affiliation: 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.
authors.forename: S Y
authors.initials: SY
authors.lastname: Wu
authors.affiliation: Department of Medicine, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
authors.forename: C V
authors.initials: CV
authors.lastname: Pecot
authors.affiliation: 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.
authors.forename: R A
authors.initials: RA
authors.lastname: Previs
authors.affiliation: 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.|Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Nagaraja
authors.affiliation: 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.
authors.forename: G N
authors.initials: GN
authors.lastname: Armaiz-Pena
authors.affiliation: 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.
authors.forename: M
authors.initials: M
authors.lastname: McGuire
authors.affiliation: 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.
authors.forename: S
authors.initials: S
authors.lastname: Pradeep
authors.affiliation: 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.|Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: L S
authors.initials: LS
authors.lastname: Mangala
authors.affiliation: Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: C
authors.identifier: 0000-0002-7880-7723
authors.initials: C
authors.lastname: Rodriguez-Aguayo
authors.affiliation: Department of Cancer Biology, Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Cancer Biology, Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Bar-Eli
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: G
authors.initials: G
authors.lastname: Lopez-Berestein
authors.affiliation: Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: G A
authors.initials: GA
authors.lastname: Calin
authors.affiliation: 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.|Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Cancer Biology, Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Sood
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008081:Liposomes; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000502:physiology*; D009369:Neoplasms / Q000209:etiology* / Q000628:therapy; D010051:Ovarian Neoplasms / Q000378:metabolism; D010713:Phosphatidylcholines / Q000008:administration & dosage; D043244:Ribonuclease III / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D008081:Liposomes; C548399:MIRN630 microRNA, human; D035683:MicroRNAs; D010713:Phosphatidylcholines; D042461:Vascular Endothelial Growth Factor A; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases; C017251:1,2-oleoylphosphatidylcholine