title: PHOX2A and PHOX2B are differentially regulated during retinoic acid-driven differentiation of SK-N-BE(2)C neuroblastoma cell line.
abstract: PHOX2B and its paralogue gene PHOX2A are two homeodomain proteins in the network regulating the development of autonomic ganglia that have been associated with the pathogenesis of neuroblastoma (NB), because of their over-expression in different NB cell lines and tumour samples. We used the SK-N-BE(2)C cell line to show that all-trans retinoic acid (ATRA), a drug that is widely used to inhibit growth and induce differentiation in NBs, regulates both PHOX2A and PHOX2B expression, albeit by means of different mechanisms: it up-regulates PHOX2A and down-regulates PHOX2B. Both mechanisms act at transcriptional level, but prolonged ATRA treatment selectively degrades the PHOX2A protein, whereas the corresponding mRNA remains up-regulated. Further, we show that PHOX2A is capable of modulating PHOX2B expression, but this mechanism is not involved in the PHOX2B down-regulation induced by retinoic acid. Our findings demonstrate that PHOX2A expression is finely controlled during retinoic acid differentiation and this, together with PHOX2B down-regulation, reinforces the idea that they may be useful biomarkers for NB staging, prognosis and treatment decision making.
authors.affiliation: Department of Medical Biotechnology and Translational Medicine (BIOMETRA), Università degli Studi di Milano, Milan, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Di Lascio
authors.affiliation: CNR - Neuroscience Institute, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Saba
authors.affiliation: Department of Medical Biotechnology and Translational Medicine (BIOMETRA), Università degli Studi di Milano, Milan, Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Belperio
authors.affiliation: San Raffaele Scientific Institute, Imaging Research Centre, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Raimondi
authors.affiliation: Department of Medical Biotechnology and Translational Medicine (BIOMETRA), Università degli Studi di Milano, Milan, Italy.
authors.forename: Helen
authors.initials: H
authors.lastname: Lucchetti
authors.affiliation: Department of Medical Biotechnology and Translational Medicine (BIOMETRA), Università degli Studi di Milano, Milan, Italy; CNR - Neuroscience Institute, Milan, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Fornasari
authors.affiliation: Department of Medical Biotechnology and Translational Medicine (BIOMETRA), Università degli Studi di Milano, Milan, Italy; CNR - Neuroscience Institute, Milan, Italy. Electronic address: r.benfante@in.cnr.it.
authors.forename: Roberta
authors.initials: R
authors.lastname: Benfante
mesh_terms: D001483:Base Sequence; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004790:Enzyme Induction / Q000187:drug effects; D004794:Enzyme Repression / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009447:Neuroblastoma; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D020218:Response Elements; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D018398:Homeodomain Proteins; C109220:NBPhox protein; C491061:PHOX2A protein, human; D014157:Transcription Factors; D014212:Tretinoin; D046988:Proteasome Endopeptidase Complex
keywords: Differentiation; Homeodomain protein; Human; Neuroblastoma; Retinoic acid; Transcription; Transcription factor