Suppressive role exerted by microRNA-29b-1-5p in triple negative breast cancer through SPIN1 regulation
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Rosa Drago-Ferrante1, Francesca Pentimalli2, Daniela Carlisi3, Anna De Blasio1, Christian Saliba4, Shawn Baldacchino5, James Degaetano6, Joseph Debono7, Gordon Caruana-Dingli7, Godfrey Grech5, Christian Scerri6,8, Giovanni Tesoriere9,11, Antonio Giordano9,10, Renza Vento1,9,11, Riccardo Di Fiore1,11
1Laboratory of Biochemistry, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Polyclinic, Palermo, Italy
2Oncology Research Center of Mercogliano (CROM), Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale”, IRCCS, Naples, Italy
3Laboratory of Biochemistry, Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, Polyclinic, Palermo, Italy
4Centre of Molecular Medicine and Biobanking, University of Malta, Msida, MSD, Malta
5Department of Pathology, Faculty of Medicine and Surgery, University of Malta, Msida, MSD, Malta
6Department of Pathology, Mater Dei Hospital, Msida, MSD, Malta
7Department of Surgery, Mater Dei Hospital, Msida, MSD, Malta
8Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, MSD, Malta
9Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA
10Department of Medicine, Surgery & Neuroscience, University of Siena, Siena, Italy
11Associazione Siciliana per la Lotta contro i Tumori (ASLOT), Palermo, Italy
Antonio Giordano, email: [email protected]
Renza Vento, email: [email protected]
Riccardo Di Fiore, email: [email protected]
Keywords: MiR-29b-1, triple-negative breast cancer, cancer stem cells, SPIN1, Wnt/β-catenin and Akt signaling pathways
Received: November 11, 2016 Accepted: February 18, 2017 Published: March 07, 2017
MiR-29 family dysregulation occurs in various cancers including breast cancers. We investigated miR-29b-1 functional role in human triple negative breast cancer (TNBC) the most aggressive breast cancer subtype. We found that miR-29b-1-5p was downregulated in human TNBC tissues and cell lines. To assess whether miR-29b-1-5p correlated with TNBC regenerative potential, we evaluated cancer stem cell enrichment in our TNBC cell lines, and found that only MDA-MB-231 and BT-20 produced primary, secondary and tertiary mammospheres, which were progressively enriched in OCT4, NANOG and SOX2 stemness genes. MiR-29b-1-5p expression inversely correlated with mammosphere stemness potential, and miR-29b-1 ectopic overexpression decreased TNBC cell growth, self-renewal, migration, invasiveness and paclitaxel resistance repressing WNT/βcatenin and AKT signaling pathways and stemness regulators. We identified SPINDLIN1 (SPIN1) among predicted miR-29b-1-5p targets. Consistently, SPIN1 was overexpressed in most TNBC tissues and cell lines and negatively correlated with miR-29b-1-5p. Target site inhibition showed that SPIN1 seems to be directly controlled by miR-29b-1-5p. Silencing SPIN1 mirrored the effects triggered by miR-29b-1 overexpression, whereas SPIN1 rescue by SPIN1miScript protector, determined the reversal of the molecular effects produced by the mimic-miR-29b-1-5p. Overall, we show that miR-29b-1 deregulation impacts on multiple oncogenic features of TNBC cells and their renewal potential, acting, at least partly, through SPIN1, and suggest that both these factors should be evaluated as new possible therapeutic targets against TNBC.
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