Linking microsomal prostaglandin E Synthase-1/PGE-2 pathway with miR-15a and -186 expression: Novel mechanism of VEGF modulation in prostate cancer.
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.
Department of Life Sciences, University of Siena, 53100, Siena, Italy.
Erika
E
Terzuoli
Department of Life Sciences, University of Siena, 53100, Siena, Italy.|Istituto Toscano Tumori (ITT), 50136, Florence, Italy.
Sandra
S
Donnini
Department of Life Sciences, University of Siena, 53100, Siena, Italy.
Federica
F
Finetti
Department of Surgery and Translational Medicine, University of Florence, 50136, Florence, Italy.
Gabriella
G
Nesi
Department of Clinical and Experimental Medicine, University of Florence, 50136, Florence, Italy.
Donata
D
Villari
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77, Stockholm, Sweden.
Hiromi
H
Hanaka
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77, Stockholm, Sweden.
Olof
O
Radmark
Department of Life Sciences, University of Siena, 53100, Siena, Italy.
Antonio
A
Giachetti
Department of Life Sciences, University of Siena, 53100, Siena, Italy.|Istituto Toscano Tumori (ITT), 50136, Florence, Italy.
Marina
M
Ziche
D000818:Animals; D045744:Cell Line, Tumor; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis*; D008861:Microsomes / Q000378:metabolism; D000071876:Prostaglandin-E Synthases / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D043244:Ribonuclease III / Q000378:metabolism; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000096:biosynthesis
C505361:MIRN15 microRNA, human; C533096:MIRN186 microRNA, human; D035683:MicroRNAs; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone
VEGF; mPGES-1/PGE-2; miR-186; prostate cancer; tumor angiogenesis