Abstract
Gain at chromosome 17q21 in neuroblastoma is associated with a poor prognosis, independent of MYCN amplification status. Several potential proto-oncogenes have been identified in this region, one of them—insulin-like growth-factor-2 mRNA binding protein (IGF2BP1)—is expressed at high levels in stage 4 tumors, and associated with overall lower patient survival. Here, we demonstrate that down-regulation of IGF2BP1 activity, either by transcript silencing or chemical inhibition, suppresses neuroblastoma cell growth. Furthermore, the combination of IGF2BP1 inhibition along with commonly used chemotherapeutics that broadly affect DNA synthesis, or cyclin-dependent kinase (CDK) inhibitors that disrupt signal transduction, have a synergistic effect on the suppression of neuroblastoma cell proliferation.
Highlights
Neuroblastoma is an embryonal tumor of the autonomic nervous system, arising from cells within neural-crest tissues [1]
With the amplification of the 17q chromosomal arm—including the IGF2BP1 gene locus—being one of the most common genetic alterations in neuroblastoma, and the linkage of IGF2BP1 expression serving as a prognosticator of poor prognosis [12, 24], we present evidence to support that IGF2BP1 is a promising novel therapeutic target for neuroblastoma
We used three different human neuroblastoma cell lines, SK-N-AS, SK-N-BE[2], and SK-N-DZ and employed both short hairpin RNA-mediated inducible knockdown or chemical inhibition of IGF2BP1 mRNA binding to test our hypothesis that suppressing IGF2BP1 activity would have a negative impact on cell growth and proliferation
Summary
Neuroblastoma is an embryonal tumor of the autonomic nervous system, arising from cells within neural-crest tissues [1]. Neuroblastoma generally occurs in young children, with the median age at diagnosis is 17 months [2], it is the most common cancer diagnosed during the first year of life [3]. The prognosis for neuroblastoma varies significantly, from tumors that regress, to those that become metastatic and resistant to therapy, often resulting in high mortality [reviewed by [4]]. Deregulation of the neural crest and the subsequent development of neuroblastoma has been linked to significant chromosomal alterations that are often associated with poor outcomes [reviewed by [6]]. Neuroblastoma tumorigenesis has long been associated with MYCN amplification at 2p24 [7]. A paralog of MYC, MYCN has a similar structure and pro-oncogenic
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