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Oncotarget. 2016 Jul 12;7(28):44350-44364. doi: 10.18632/oncotarget.10051.

Linking microsomal prostaglandin E Synthase-1/PGE-2 pathway with miR-15a and -186 expression: Novel mechanism of VEGF modulation in prostate cancer.

Author information

1
Department of Life Sciences, University of Siena, 53100, Siena, Italy.
2
Istituto Toscano Tumori (ITT), 50136, Florence, Italy.
3
Department of Surgery and Translational Medicine, University of Florence, 50136, Florence, Italy.
4
Department of Clinical and Experimental Medicine, University of Florence, 50136, Florence, Italy.
5
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77, Stockholm, Sweden.

Abstract

Prostaglandin E-2 (PGE-2) promotes tumor angiogenesis via paracrine secretion of pro-angiogenic growth factors, such as vascular endothelial growth factor (VEGF). Since miRNAs regulate several cell processes, including angiogenesis, we sought to determine whether they would influence PGE-2-induced VEGF. We compared DU145 and PC3 prostate cancer cells bearing the mPGES-1 enzyme (mPGES-1+/+) and producing PGE-2, with those in which the enzyme was silenced or deleted (mPGES-1-/-). We demonstrated that mPGES-1/PGE-2 signaling decreased Dicer expression and miRNA biogenesis. Genome-wide sequencing of miRNAs revealed that miR-15a and miR-186, associated with expression of VEGF and hypoxia inducible factor-1α (HIF-1α), were down-regulated in mPGES-1+/+ cells. As a consequence, mPGES-1+/+ tumor cells expressed high levels of VEGF and HIF-1α, induced endothelial cells activation and formed highly vascularized tumors. Mir-186 mimic inhibited VEGF expression in mPGES-1+/+ tumor xenografts and reduced tumor growth. In human prostate cancer specimens, mPGES-1 was over-expressed in tumors with high Gleason score, elevated expression of VEGF and HIF-1α, high microvessel density and decreased expression of Dicer, miR15a and miR-186. Thus, clear evidence for regulating miRNA processing and VEGF output by intrinsic PGE-2 production provides a means to distinguish between aggressive and indolent prostate tumors and suggests a potential target for controlling tumor progression.

KEYWORDS:

VEGF; mPGES-1/PGE-2; miR-186; prostate cancer; tumor angiogenesis

PMID:
27322147
PMCID:
PMC5190102
DOI:
10.18632/oncotarget.10051
[Indexed for MEDLINE]
Free PMC Article

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