miR-214 and miR-148b Targeting Inhibits Dissemination of Melanoma and Breast Cancer.
miR-214 and miR-148b have been proposed to antagonize the effects of each other in enabling or blocking metastasis, respectively. In this study, we provide evidence deepening their role and interrelationship in the process of metastatic dissemination. Depleting miR-214 or elevating miR-148b blocked the dissemination of melanoma or breast cancer cells, an effect that could be accentuated by dual alteration. Mechanistic investigations indicated that dual alteration suppressed passage of malignant cells through the blood vessel endothelium by reducing expression of the cell adhesion molecules ITGA5 and ALCAM. Notably, transendothelial migration in vitro and extravasation in vivo impaired by singly alternating miR-214 or miR-148b could be overridden by overexpression of ITGA5 or ALCAM in the same tumor cells. In clinical specimens of primary breast cancer or metastatic melanoma, we found a positive correlation between miR-214 and ITGA5 or ALCAM along with an inverse correlation of miR-214 and miR-148b in the same specimens. Our findings define an antagonistic relationship of miR-214 and miR-148b in determining the dissemination of cancer cells via tumor-endothelial cell interactions, with possible implications for microRNA-mediated therapeutic interventions aimed at blocking cancer extravasation. Cancer Res; 76(17); 5151-62. ©2016 AACR.
Molecular Biotechnology Center (MBC), University of Torino, Torino, Italy. Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. Center for Complex Systems in Molecular Biology and Medicine, University of Torino, Torino, Italy.
Francesca
F
Orso
Molecular Biotechnology Center (MBC), University of Torino, Torino, Italy. Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
Lorena
L
Quirico
Molecular Biotechnology Center (MBC), University of Torino, Torino, Italy. Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
Federico
F
Virga
Molecular Biotechnology Center (MBC), University of Torino, Torino, Italy. Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
Elisa
E
Penna
Molecular Biotechnology Center (MBC), University of Torino, Torino, Italy. Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
Daniela
D
Dettori
Molecular Biotechnology Center (MBC), University of Torino, Torino, Italy. Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. Center for Complex Systems in Molecular Biology and Medicine, University of Torino, Torino, Italy.
Daniela
D
Cimino
Molecular Biotechnology Center (MBC), University of Torino, Torino, Italy. Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
Roberto
R
Coppo
Molecular Biotechnology Center (MBC), University of Torino, Torino, Italy. Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
Elena
E
Grassi
Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
Angela Rita
AR
Elia
Department of Medical Sciences, University of Torino, Torino, Italy. Immunogenetics Unit, Human Genetics Foundation, Torino, Italy.
Davide
D
Brusa
Department of Medical Sciences, University of Torino, Torino, Italy. Immunogenetics Unit, Human Genetics Foundation, Torino, Italy.
Silvia
S
Deaglio
Department of Medical Sciences, University of Torino, Torino, Italy.
Maria Felice
MF
Brizzi
Friederich Miescher Institute and Swiss Institute of Bioinformatics, Basel, Switzerland.
Michael B
MB
Stadler
Molecular Biotechnology Center (MBC), University of Torino, Torino, Italy. Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. Center for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, Milan, Italy.
Paolo
P
Provero
Center for Complex Systems in Molecular Biology and Medicine, University of Torino, Torino, Italy. Department of Physics University of Torino, Torino, Italy.
Michele
M
Caselle
Molecular Biotechnology Center (MBC), University of Torino, Torino, Italy. Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy. Center for Complex Systems in Molecular Biology and Medicine, University of Torino, Torino, Italy. daniela.taverna@unito.it.
Daniela
D
Taverna
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D015816:Cell Adhesion Molecules, Neuronal / Q000096:biosynthesis; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D042783:Endothelial Cells / Q000473:pathology; D005260:Female; D005326:Fetal Proteins / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D064593:Heterografts; D006801:Humans; D015151:Immunoblotting; D008545:Melanoma / Q000235:genetics / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics*; D009361:Neoplasm Invasiveness / Q000235:genetics*; D020410:Activated-Leukocyte Cell Adhesion Molecule
D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D015816:Cell Adhesion Molecules, Neuronal; D005326:Fetal Proteins; D035683:MicroRNAs; C105613:ALCAM protein, human; D020410:Activated-Leukocyte Cell Adhesion Molecule; C547397:MIRN214 microRNA, human