Linking microsomal prostaglandin E synthase-1/PGE-2 pathway with miR-15a and -186 expression: Novel mechanism of VEGF modulation in prostate cancer
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Erika Terzuoli1,*, Sandra Donnini1,2,*, Federica Finetti1, Gabriella Nesi3, Donata Villari4, Hiromi Hanaka5, Olof Radmark5, Antonio Giachetti1, Marina Ziche1,2
1Department of Life Sciences, University of Siena, 53100, Siena, Italy
2Istituto Toscano Tumori (ITT), 50136, Florence, Italy
3Department of Surgery and Translational Medicine, University of Florence, 50136, Florence, Italy
4Department of Clinical and Experimental Medicine, University of Florence, 50136, Florence, Italy
5Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77, Stockholm, Sweden
*These authors contributed equally to this work
Marina Ziche, email: [email protected]
Keywords: miR-186, mPGES-1/PGE-2, VEGF, prostate cancer, tumor angiogenesis
Received: January 12, 2016 Accepted: June 01, 2016 Published: June 14, 2016
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.
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