title: Inhibition of hypoxia inducible factors combined with all-trans retinoic acid treatment enhances glial transdifferentiation of neuroblastoma cells.
abstract: Neuroblastoma (NBL) is a heterogeneous tumor characterized by a wide range of clinical manifestations. A high tumor cell differentiation grade correlates to a favorable stage and positive outcome. Expression of the hypoxia inducible factors HIF1-α (HIF1A gene) and HIF2-α (EPAS1 gene) and/or hypoxia-regulated pathways has been shown to promote the undifferentiated phenotype of NBL cells. Our hypothesis is that HIF1A and EPAS1 expression represent one of the mechanisms responsible for the lack of responsiveness of NBL to differentiation therapy. Clinically, high levels of HIF1A and EPAS1 expression were associated with inferior survival in two NBL microarray datasets, and patient subgroups with lower expression of HIF1A and EPAS1 showed significant enrichment of pathways related to neuronal differentiation. In NBL cell lines, the combination of all-trans retinoic acid (ATRA) with HIF1A or EPAS1 silencing led to an acquired glial-cell phenotype and enhanced expression of glial-cell differentiation markers. Furthermore, HIF1A or EPAS1 silencing might promote cell senescence independent of ATRA treatment. Taken together, our data suggest that HIF inhibition coupled with ATRA treatment promotes differentiation into a more benign phenotype and cell senescence in vitro. These findings open the way for additional lines of attack in the treatment of NBL minimal residue disease.
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Naples, Italy.|CEINGE Biotecnologie Avanzate, Naples, Italy.
authors.forename: Flora
authors.initials: F
authors.lastname: Cimmino
authors.affiliation: CEINGE Biotecnologie Avanzate, Naples, Italy.|Scuola di Medicina e Chirurgia, Università degli Studi di Verona, Verona, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Pezone
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Naples, Italy.|CEINGE Biotecnologie Avanzate, Naples, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Avitabile
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Naples, Italy.|CEINGE Biotecnologie Avanzate, Naples, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Acierno
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Naples, Italy.|CEINGE Biotecnologie Avanzate, Naples, Italy.
authors.forename: Immacolata
authors.initials: I
authors.lastname: Andolfo
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Naples, Italy.|CEINGE Biotecnologie Avanzate, Naples, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Capasso
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Naples, Italy.|CEINGE Biotecnologie Avanzate, Naples, Italy.
authors.forename: Achille
authors.initials: A
authors.lastname: Iolascon
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects*; D020868:Gene Silencing; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics; D009447:Neuroblastoma / Q000235:genetics / Q000473:pathology*; D009457:Neuroglia / Q000187:drug effects*; D016896:Treatment Outcome; D014212:Tretinoin / Q000494:pharmacology*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014212:Tretinoin; D000099162:Endothelial PAS Domain-Containing Protein 1