CHL1 gene acts as a tumor suppressor in human neuroblastoma
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Marzia Ognibene1,*, Gabriella Pagnan2,8,*, Danilo Marimpietri1, Davide Cangelosi3, Michele Cilli4, Maria Chiara Benedetti5, Renata Boldrini5, Alberto Garaventa7, Francesco Frassoni1, Alessandra Eva3, Luigi Varesio3,#, Vito Pistoia6 and Annalisa Pezzolo1
1Laboratorio Cellule Staminali Post Natali e Terapie Cellulari, Istituto Giannina Gaslini, Genova, Italy
2Laboratorio di Oncologia, Istituto Giannina Gaslini, Genova, Italy
3Laboratorio di Biologia Molecolare, Istituto Giannina Gaslini, Genova, Italy
4Animal Model Facility, IRCCS Azienda Ospedaliera Universitaria San Martino, IST, Istituto per la Ricerca sul Cancro, Genova, Italy
5Laboratorio di Anatomia Patologica, Ospedale Pediatrico Bambino Gesù, Roma, Italy
6Area di Immunologia, Ospedale Pediatrico Bambino Gesù, Roma, Italy
7Divisione di Oncologia, Istituto Giannina Gaslini, Genova, Italy
8Present address: Laboratorio di Immunologia Clinica e Sperimentale, Istituto Giannina Gaslini, Genova, Italy
*These authors contributed equally to this work
#Dedicated to this author who has recently passed away
Annalisa Pezzolo, email: firstname.lastname@example.org
Keywords: neuroblastoma; CHL1 gene; differentiation; apoptosis; autophagy
Received: January 10, 2018 Accepted: April 28, 2018 Published: May 25, 2018
Neuroblastoma is an aggressive, relapse-prone childhood tumor of the sympathetic nervous system that accounts for 15% of pediatric cancer deaths. A distal portion of human chromosome 3p is often deleted in neuroblastoma, this region may contain one or more putative tumor suppressor genes. A 2.54 Mb region at 3p26.3 encompassing the smallest region of deletion pinpointed CHL1 gene, the locus for neuronal cell adhesion molecule close homolog of L1. We found that low CHL1 expression predicted poor outcome in neuroblastoma patients. Here we have used two inducible cell models to analyze the impact of CHL1 on neuroblastoma biology. Over-expression of CHL1 induced neurite-like outgrowth and markers of neuronal differentiation in neuroblastoma cells, halted tumor progression, inhibited anchorage-independent colony formation, and suppressed the growth of human tumor xenografts. Conversely, knock-down of CHL1 induced neurite retraction and activation of Rho GTPases, enhanced cell proliferation and migration, triggered colony formation and anchorage-independent growth, accelerated growth in orthotopic xenografts mouse model. Our findings demonstrate unambiguously that CHL1 acts as a regulator of proliferation and differentiation of neuroblastoma cells through inhibition of the MAPKs and Akt pathways. CHL1 is a novel candidate tumor suppressor in neuroblastoma, and its associated pathways may represent a promising target for future therapeutic interventions.
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