Phox2B correlates with MYCN and is a prognostic marker for neuroblastoma development

Abstract

Abstract. Neuroblastoma is the one of the most common extracranial childhood malignancies, accounting for ~15% of tumor-associated deaths in children. It is generally considered that neuroblastoma originates from neural crest cells in the paravertebral sympathetic ganglia and the adrenal medulla. However, the mechanism by which neuroblastoma arises during sympathetic neurogenesis and the cellular mechanism that drives neuroblastoma development remains unclear. The present study investigated the cell components during neuroblastoma development in the tyrosine hydroxylase-v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (TH-MYCN) mouse model, a transgenic mouse model of human neuroblastoma. The present study demonstrates that paired-like homeobox 2b (Phox2B) + neuronal progenitors are the major cellular population in hyperplastic lesions and primary tumors. In addition, Phox2B + neuronal progenitors in hyperplastic lesions or primary tumors were observed to be in an actively proliferative and undifferentiated state. The current study also demonstrated that high expression levels of Phox2B promotes neuroblastoma cell proliferation and xenograft tumor growth. These findings indicate that the proliferation of undifferentiated Phox2B + neuronal progenitors is a cellular mechanism that promotes neuroblastoma development and indicates that Phox2B is a critical regulator in neuroblastoma pathogenesis.

Enhanced expression of MycN/CIP2A drives neural crest toward a neural stem cell-like fate: Implications for priming of neuroblastoma

“…Following neural crest EMT from the CNS, MycN is expressed only at very low levels in migrating neural crest cells (9,13) and appears to be further down-regulated before the cells coalesce to form ganglia. Later, it has been reported to be reexpressed in differentiating sympathetic ganglia after the onset of the expression of proneural genes such as ASCL1 (MASH1/HASH1) and lineagedetermining factors such as Phox2B and Hand2 (14)(15)(16)(17)(18)(19)(20)(21). Some data suggest that the initiation of MycN expression in the ganglia is concomitant with Phox2a expression, followed by Gata2/3, the Trk genes, and the noradrenergic enzymes tyrosine hydroxylase (TH) and dopamine beta hydroxylase (DβH) that are associated with Significance Neuroblastoma is a neural crest-derived pediatric cancer that develops in the embryonic peripheral nervous system (PNS).…”

“…terminal differentiation and functionality of sympathetic neurons (22)(23)(24), although this remains controversial (9,(25)(26)(27). Postnatally, MycN is not expressed in the sympathetic ganglia (16). Importantly, overexpression of MycN in mouse sympathoadrenal progenitors in vivo is not sufficient for tumor formation but instead results in increased neural differentiation (28).…”

Causative and common PHOX2B variants define a broad phenotypic spectrum

“…However, in most NB cells PHOX2B is highly expressed rather than down‐regulated . In particular, PHOX2B gene expression correlates with MYCN levels and both are reliable markers for unfavorable NB prognosis …”

“…70 In particular, PHOX2B gene expression correlates with MYCN levels and both are reliable markers for unfavorable NB prognosis. [71][72][73] PHOX2B overexpression in NB may be ascribed to different causes, among which the lack of miR-204-mediated down-regulation of its mRNA, due to reduced miR-204 expression in NB samples. 25,74 miR-204 has recently revealed to be a key microRNA in NB development as, in addition to PHOX2B, also MYCN has been identified among its target genes, 75 thus suggesting an interplay among PHOX2B, Figure 2) are found in PHOX2B-related diseases with a certain frequency.…”

PHOX2A and PHOX2B are differentially regulated during retinoic acid-driven differentiation of SK-N-BE(2)C neuroblastoma cell line

“…The pathogenetic role of PHOX2B in NB is supported by the presence of heterozygous mutations in familial, sporadic and syndromic cases of NB, and its over-expression in tumour samples and NB cell lines, sometimes associated with other neurochristopathies such as Congenital Central Hypoventilation Syndrome (CCHS) and Hirschprung's disease (HSCR) [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] , but the underlying mechanisms are still largely unknown. In vitro and in vivo studies have linked the PHOX2B mutations associated with NB with the impaired differentiation of immature sympathetic neurons that can proliferate, and aberrant differentiation towards the glial lineage [10] , [24] .…”