miR-135b suppresses tumorigenesis in glioblastoma stem-like cells impairing proliferation, migration and self-renewal

// Valentina Lulli 1,* , Mariachiara Buccarelli 1,* , Maurizio Martini 2 , Michele Signore 1 , Mauro Biffoni 1 , Stefano Giannetti 3 , Liliana Morgante 3 , Giovanna Marziali 1 , Ramona Ilari 1 , Alfredo Pagliuca 1 , Luigi Maria Larocca 2 , Ruggero De Maria 4 , Roberto Pallini 5,** and Lucia Ricci-Vitiani 1,** 1 Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy 2 Institute of Anatomic Pathology, Università Cattolica del Sacro Cuore, Rome, Italy 3 Institute of Human Anatomy, Università Cattolica del Sacro Cuore, Rome, Italy 4 Regina Elena National Cancer Institute, Rome, Italy 5 Institute of Neurosurgery, Università Cattolica del Sacro Cuore, Rome, Italy * These authors have contributed equally to this work ** These two authors shared senior authorship Correspondence to: Lucia Ricci-Vitiani, email: // Keywords : ADAM12, SMAD5, GSK3β, miRNAs, glioblastoma, glioblastoma stem cells Received : April 21, 2015 Accepted : September 17, 2015 Published : September 30, 2015 Abstract Glioblastoma multiforme (GBM) is the most common and fatal malignant adult primary brain tumor. Currently, the overall prognosis for GBM patients remains poor despite advances in neurosurgery and adjuvant treatments. MicroRNAs (miRNAs) contribute to the pathogenesis of various types of tumor, including GBM. In this study we analyzed the expression of a panel of miRNAs, which are known to be differentially expressed by the brain and GBM tumor, in a collection of patient-derived GBM stem-like cells (GSCs). Notably, the average expression level of miR-135b, was the most downregulated compared to its normal counterpart, suggesting a potential role as anti-oncogene. Restoration of miR-135b in GSCs significantly decreased proliferation, migration and clonogenic abilities. More importantly, miR-135b restoration was able to significantly reduce brain infiltration in mouse models of GBM obtained by intracerebral injection of GSC lines. We identified ADAM12 and confirmed SMAD5 and GSK3β as miR-135b targets and potential mediators of its effects. The whole transcriptome analysis ascertained that the expression of miR-135b downmodulated additional genes driving key pathways in GBM survival and infiltration capabilities. Our results identify a critical role of miR-135b in the regulation of GBM development, suggesting that miR-135b might act as a tumor-suppressor factor and thus providing a potential candidate for the treatment of GBM patients.