Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 25903-25921 |
| Number of pages | 19 |
| Journal | Oncotarget |
| Volume | 9 |
| Issue number | 40 |
| DOIs | |
| Publication status | Published - Jan 1 2018 |
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Keywords
- Apoptosis
- Autophagy
- CHL1 gene
- Differentiation
- Neuroblastoma
ASJC Scopus subject areas
- Oncology
Cite this
CHL1 gene acts as a tumor suppressor in human neuroblastoma. / Ognibene, Marzia; Pagnan, Gabriella; Marimpietri, Danilo; Cangelosi, Davide; Cilli, Michele; Benedetti, Maria Chiara; Boldrini, Renata; Garaventa, Alberto; Frassoni, Francesco; Eva, Alessandra; Varesio, Luigi; Pistoia, Vito; Pezzolo, Annalisa.
In: Oncotarget, Vol. 9, No. 40, 01.01.2018, p. 25903-25921.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - CHL1 gene acts as a tumor suppressor in human neuroblastoma
AU - Ognibene, Marzia
AU - Pagnan, Gabriella
AU - Marimpietri, Danilo
AU - Cangelosi, Davide
AU - Cilli, Michele
AU - Benedetti, Maria Chiara
AU - Boldrini, Renata
AU - Garaventa, Alberto
AU - Frassoni, Francesco
AU - Eva, Alessandra
AU - Varesio, Luigi
AU - Pistoia, Vito
AU - Pezzolo, Annalisa
PY - 2018/1/1
Y1 - 2018/1/1
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Autophagy
KW - CHL1 gene
KW - Differentiation
KW - Neuroblastoma
UR - http://www.scopus.com/inward/record.url?scp=85047445553&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85047445553&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.25403
DO - 10.18632/oncotarget.25403
M3 - Article
VL - 9
SP - 25903
EP - 25921
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 40
ER -