Down-regulation of the Lamin A/C in neuroblastoma triggers the expansion of tumor initiating cells

// Marta Nardella 1 , Loredana Guglielmi 1 , Carla Musa 1 , Ilaria Iannetti 1 , Giovanna Maresca 1 , Donatella Amendola 2 , Manuela Porru 3 , Elisabetta Carico 4 , Giuseppe Sessa 5 , Rosalba Camerlingo 5 , Carlo Dominici 6, 7 , Francesca Megiorni 6 , Marika Milan 1 , Claudia Bearzi 1, 8 , Roberto Rizzi 1, 8 , Giuseppe Pirozzi 5 , Carlo Leonetti 3 , Barbara Bucci 2 , Delio Mercanti 1 , Armando Felsani 1 , Igea D'Agnano 1 1 Institute of Cell Biology and Neurobiology-CNR, Monterotondo, Rome, Italy 2 S.Pietro Hospital Fatebenefratelli, Rome, Italy 3 Regina Elena Cancer Institute, Rome, Italy 4 UOD Cytopathology, Department of Molecular and Clinical Medicine, Faculty of Medicine and Psychology, Sapienza University, Rome, Italy 5 Department of Experimental Oncology, National Cancer Institute–IRCCS “Fondazione G. Pascale”, Naples, Italy 6 Department of Paediatrics and Infantile Neuropsychiatry, Sapienza University, Rome, Italy 7 School of Reproductive and Developmental Medicine, University of Liverpool, Liverpool, United Kingdom 8 I.R.C.C.S Multimedica, Scientific and Technology Pole, Milan, Italy Correspondence to: Igea D'Agnano, e-mail: igea.dagnano@cnr.it Keywords: neuroblastoma, TICs, Lamin A/C, MYCN, miRNAs Received: April 09, 2015      Accepted: August 21, 2015      Published: September 03, 2015 ABSTRACT Tumor-initiating cells constitute a population within a tumor mass that shares properties with normal stem cells and is considered responsible for therapy failure in many cancers. We have previously demonstrated that knockdown of the nuclear envelope component Lamin A/C in human neuroblastoma cells inhibits retinoic acid-mediated differentiation and results in a more aggressive phenotype. In addition, Lamin A/C is often lost in advanced tumors and changes in the nuclear envelope composition occur during tumor progression. Based on our previous data and considering that Lamin A/C is expressed in differentiated tissues, we hypothesize that the lack of Lamin A/C could predispose cells toward a stem-like phenotype, thus influencing the development of tumor-initiating cells in neuroblastoma. This paper demonstrates that knockdown of Lamin A/C triggers the development of a tumor-initiating cell population with self-renewing features in human neuroblastoma cells. We also demonstrates that the development of TICs is due to an increased expression of MYCN gene and that in neuroblastoma exists an inverse relationship between LMNA and MYCN expression.