Oncotarget

Research Papers:

PHOX2B is a suppressor of neuroblastoma metastasis

Osnat Naftali, Shelly Maman, Tsipi Meshel, Orit Sagi-Assif, Ravit Ginat and Isaac P. Witz _

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Oncotarget. 2016; 7:10627-10637. https://doi.org/10.18632/oncotarget.7056

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Abstract

Osnat Naftali1, Shelly Maman1, Tsipi Meshel1, Orit Sagi-Assif1, Ravit Ginat1, Isaac P. Witz1

1Department of Cell Research and Immunology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel 69978

Correspondence to:

Isaac P. Witz, e-mail: isaacw@tauex.tau.ac.il

Keywords: PHOX2B, minimal residual disease, metastasis, neuroblastoma, methylation

Received: December 17, 2015    Accepted: January 23, 2016    Published: January 28, 2016

ABSTRACT

Paired like homeobox 2B (PHOX2B) is a minimal residual disease (MRD) marker of neuroblastoma. The presence of MRD, also referred to as micro-metastases, is a powerful marker of poor prognosis in neuroblastoma.

Lung metastasis is considered a terminal event in neuroblastoma. Lung micro-metastatic neuroblastoma (MicroNB) cells show high expression levels of PHOX2B and possess a less malignant and metastatic phenotype than lung macro metastatic neuroblastoma (MacroNB) cells, which hardly express PHOX2B.

In vitro assays showed that PHOX2B knockdown in MicroNB cells did not affect cell viability; however it decreased the migratory capacity of the MicroNB-shPHOX2B cells. An orthotopic inoculation of MicroNB-shPHOX2B cells into the adrenal gland of nude mice resulted in significantly larger primary tumors and a heavier micro-metastatic load in the lungs and bone-marrow, than when control cells were inoculated.

PHOX2B expression was found to be regulated by methylation. The PHOX2B promoter in MacroNB cells is significantly more methylated than in MicroNB cells. Demethylation assays using 5-azacytidine demonstrated that methylation can indeed inhibit PHOX2B transcription in MacroNB cells.

These pre-clinical data strongly suggest that PHOX2B functions as a suppressor of neuroblastoma progression.


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