Down-regulation of the Lamin A/C in neuroblastoma triggers the expansion of tumor initiating cells
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Marta Nardella1, Loredana Guglielmi1, Carla Musa1, Ilaria Iannetti1, Giovanna Maresca1, Donatella Amendola2, Manuela Porru3, Elisabetta Carico4, Giuseppe Sessa5, Rosalba Camerlingo5, Carlo Dominici6,7, Francesca Megiorni6, Marika Milan1, Claudia Bearzi1,8, Roberto Rizzi1,8, Giuseppe Pirozzi5, Carlo Leonetti3, Barbara Bucci2, Delio Mercanti1, Armando Felsani1, Igea D'Agnano1
1Institute of Cell Biology and Neurobiology-CNR, Monterotondo, Rome, Italy
2S.Pietro Hospital Fatebenefratelli, Rome, Italy
3Regina Elena Cancer Institute, Rome, Italy
4UOD Cytopathology, Department of Molecular and Clinical Medicine, Faculty of Medicine and Psychology, Sapienza University, Rome, Italy
5Department of Experimental Oncology, National Cancer Institute–IRCCS “Fondazione G. Pascale”, Naples, Italy
6Department of Paediatrics and Infantile Neuropsychiatry, Sapienza University, Rome, Italy
7School of Reproductive and Developmental Medicine, University of Liverpool, Liverpool, United Kingdom
8I.R.C.C.S Multimedica, Scientific and Technology Pole, Milan, Italy
Igea D'Agnano, e-mail: [email protected]
Keywords: neuroblastoma, TICs, Lamin A/C, MYCN, miRNAs
Received: April 09, 2015 Accepted: August 21, 2015 Published: September 03, 2015
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.
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