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Proc Natl Acad Sci U S A. 2015 Mar 24;112(12):3770-5. doi: 10.1073/pnas.1500008112. Epub 2015 Mar 9.

Synchronous down-modulation of miR-17 family members is an early causative event in the retinal angiogenic switch.

Author information

1
Laboratory of Medical Genomics, A. C. Camargo Cancer Center, São Paulo 01509-010, Brazil;
2
Laboratory of Medical Genomics, A. C. Camargo Cancer Center, São Paulo 01509-010, Brazil; Laboratory of Neurosciences, Institute of Psychiatry, University of São Paulo Medical School, São Paulo 05403, Brazil;
3
University of New Mexico Cancer Center and Divisions of Molecular Medicine and.
4
Genitourinary Medical Oncology, David H. Koch Center and.
5
Department of Biochemistry.
6
Laboratory of Bioinformatics and Computational Biology, Division of Clinical and Translational Research, National Cancer Institute, Rio de Janeiro 20231, Brazil;
7
Candiolo Cancer Institute-Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) and Department of Oncology, University of Turin, Candiolo,10060, Italy; and.
8
Institute of Psychiatry, and.
9
Institute of Mathematics and Statistics, University of São Paulo, São Paulo 05508, Brazil;
10
Department of Experimental Therapeutics and Center for RNA Interference and Non-Coding RNAs, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030;
11
Harvard Medical School and Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA 02215 richard_sidman@hms.harvard.edu warap@salud.unm.edu rpasqual@salud.unm.edu.
12
University of New Mexico Cancer Center and Divisions of Hematology and Oncology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131; richard_sidman@hms.harvard.edu warap@salud.unm.edu rpasqual@salud.unm.edu.
13
University of New Mexico Cancer Center and Divisions of Molecular Medicine and richard_sidman@hms.harvard.edu warap@salud.unm.edu rpasqual@salud.unm.edu.

Abstract

Six members of the microRNA-17 (miR-17) family were mapped to three different chromosomes, although they share the same seed sequence and are predicted to target common genes, among which are those encoding hypoxia-inducible factor-1α (HIF1A) and VEGFA. Here, we evaluated the in vivo expression profile of the miR-17 family in the murine retinopathy of prematurity (ROP) model, whereby Vegfa expression is highly enhanced at the early stage of retinal neovascularization, and we found simultaneous reduction of all miR-17 family members at this stage. Using gene reporter assays, we observed binding of these miRs to specific sites in the 3' UTRs of Hif1a and Vegfa. Furthermore, overexpression of these miRs decreased HIF1A and VEGFA expression in vitro. Our data indicate that this miR-17 family elicits a regulatory synergistic down-regulation of Hif1a and Vegfa expression in this biological model. We propose the existence of a coordinated regulatory network, in which diverse miRs are synchronously regulated to target the Hif1a transcription factor, which in turn, potentiates and reinforces the regulatory effects of the miRs on Vegfa to trigger and sustain a significant physiological response.

KEYWORDS:

eye; hypoxia; miRNA family; miRNA regulatory network; mouse neovascularization model

PMID:
25775553
PMCID:
PMC4378441
DOI:
10.1073/pnas.1500008112
[Indexed for MEDLINE]
Free PMC Article

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