Proteomic Alterations in Response to Hypoxia Inducible Factor 2α in Normoxic Neuroblastoma Cells.
Hypoxia inducible factor (HIF)-2α protein expression in solid tumors promotes stem-like phenotype in cancer stem cells and increases tumorigenic potential in nonstem cancer cells. Recently, we have shown that HIF-1/2α gene expression is correlated to neuroblastoma (NB) poor survival and to undifferentiated tumor state; HIF-2α protein was demonstrated to enhance aggressive features of the disease. In this study, we used proteomic experiments on NB cells to investigate HIF-2α downstream-regulated proteins or pathways with the aim of providing novel therapeutic targets or bad prognosis markers. We verified that pathways mostly altered by HIF-2α perturbation are involved in tumor progression. In particular, HIF-2α induces alteration of central metabolism and splicing control pathways. Simultaneously, WNT, RAS/MAPK, and PI3K/AKT activity or expression are affected and may impact the sensitivity and the intensity of HIF-2α-regulated pathways. Furthermore, genes coding the identified HIF-2α-related markers built a signature able to stratify NB patients with unfavorable outcome. Taken together, our findings underline the relevance of dissecting the downstream effects of a poor survival marker in developing targeted therapy and improving patient stratification. Future prospective studies are needed to translate the use of these data into the clinical practice.
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II" , via Pansini, 5, 80131 Naples, Italy.|CEINGE Biotecnologie Avanzate , Via Gaetano Salvatore 486, 80145 Naples, Italy.
Flora
F
Cimmino
CEINGE Biotecnologie Avanzate , Via Gaetano Salvatore 486, 80145 Naples, Italy.|Scuola di Medicina e Chirurgia, Università degli Studi di Verona , 37129 Verona, Italy.
Lucia
L
Pezone
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II" , via Pansini, 5, 80131 Naples, Italy.|CEINGE Biotecnologie Avanzate , Via Gaetano Salvatore 486, 80145 Naples, Italy.
Marianna
M
Avitabile
Istituto di Ricerca Pediatrica Città della Speranza - IRP , 35121 Padua, Italy.
Luca
L
Persano
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II" , via Pansini, 5, 80131 Naples, Italy.|CEINGE Biotecnologie Avanzate , Via Gaetano Salvatore 486, 80145 Naples, Italy.
Monica
M
Vitale
Proteomics and Mass Spectrometry Laboratory, ISPAAM, National Research Council , 80147 Naples, Italy.
Mauro
M
Sassi
Dipartimento di Salute della Donna e del Bambino, Università degli Studi di Padova , 35128 Padua, Italy.
Silvia
S
Bresolin
Dipartimento di Salute della Donna e del Bambino, Università degli Studi di Padova , 35128 Padua, Italy.
Valentina
V
Serafin
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II" , via Pansini, 5, 80131 Naples, Italy.|CEINGE Biotecnologie Avanzate , Via Gaetano Salvatore 486, 80145 Naples, Italy.
Nicola
N
Zambrano
Proteomics and Mass Spectrometry Laboratory, ISPAAM, National Research Council , 80147 Naples, Italy.
Andrea
A
Scaloni
Dipartimento di Salute della Donna e del Bambino, Università degli Studi di Padova , 35128 Padua, Italy.
Giuseppe
G
Basso
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II" , via Pansini, 5, 80131 Naples, Italy.|CEINGE Biotecnologie Avanzate , Via Gaetano Salvatore 486, 80145 Naples, Italy.
Achille
A
Iolascon
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II" , via Pansini, 5, 80131 Naples, Italy.|CEINGE Biotecnologie Avanzate , Via Gaetano Salvatore 486, 80145 Naples, Italy.
Mario
M
Capasso
D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D014408:Biomarkers, Tumor; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053858:Metabolic Networks and Pathways; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D040901:Proteomics / Q000379:methods*; D016019:Survival Analysis; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D000099162:Endothelial PAS Domain-Containing Protein 1
hypoxia inducible factor 2α; neuroblastoma; patient stratification; proteomics