Research Papers:

Targeting of PHOX2B expression allows the identification of drugs effective in counteracting neuroblastoma cell growth

Eleonora Di Zanni, Giovanna Bianchi, Roberto Ravazzolo, Lizzia Raffaghello, Isabella Ceccherini and Tiziana Bachetti _

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Oncotarget. 2017; 8:72133-72146. https://doi.org/10.18632/oncotarget.19922

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Eleonora Di Zanni1,4, Giovanna Bianchi2, Roberto Ravazzolo1,3, Lizzia Raffaghello2, Isabella Ceccherini1 and Tiziana Bachetti1

1U.O.C. Genetica Medica, Istituto Giannina Gaslini, Genova, Italy

2Laboratorio di Oncologia, IRCCS G. Gaslini, Genova, Italy

3Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health and CEBR, Università degli Studi di Genova, Genova, Italy

4Present Address: Istituto di Biofisica, CNR, Genova, Italy

Correspondence to:

Tiziana Bachetti, email: [email protected]

Keywords: PHOX2B, ALK, neuroblastoma, gene expression regulation, drug screening

Received: October 25, 2016     Accepted: July 18, 2017     Published: August 04, 2017


The pathogenic role of the PHOX2B gene in neuroblastoma is indicated by heterozygous mutations in neuroblastoma patients and by gene overexpression in both neuroblastoma cell lines and tumor samples.

PHOX2B encodes a transcription factor which is crucial for the correct development and differentiation of sympathetic neurons.

PHOX2B overexpression is considered a prognostic marker for neuroblastoma and it is also used by clinicians to monitor minimal residual disease. Furthermore, it has been observed that neuronal differentiation in neuroblastoma is dependent on down-regulation of PHOX2B expression, which confirms that PHOX2B expression may be considered a target in neuroblastoma.

Here, PHOX2B promoter or 3′ untranslated region were used as molecular targets in an in vitro high-throughput approach that led to the identification of molecules able to decrease PHOX2B expression at transcriptional and likely even at post-transcriptional levels. Further functional investigations carried out on PHOX2B mRNA levels and biological consequences, such as neuroblastoma cell apoptosis and growth, showed that chloroquine and mycophenolate mofetil are most promising agents for neuroblastoma therapy based on down-regulation of PHOX2B expression.

Finally, a strong correlation between the effect of drugs in terms of down-regulation of PHOX2B expression and of biological consequences in neuroblastoma cells confirms the role of PHOX2B as a potential molecular target in neuroblastoma.

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