Proteomic alterations in response to Hypoxia Inducible Factor 2# in normoxic Neuroblastoma cells.

Hypoxia Inducible Factor (HIF)-2? protein expression in solid tumors promotes stem-like phenotype in cancer stem cells and increases tumorigenic potential in non-stem cancer cells. Recently, we have shown HIF-1/2? gene expression is correlated to neuroblastoma (NB) poor survival and to undifferentiated tumor state; HIF-2? protein was demonstrated to enhance aggressive features of the disease. In this study, we used proteomic experiments on NB cells to investigate HIF-2? downstream-regulated proteins and/or pathways with the aim of providing novel therapeutic targets and/or bad prognosis markers. We verified that pathways mostly altered by HIF-2? perturbation are involved in tumor progression. In particular, HIF-2? induces alteration of central metabolism and splicing control pathways. Simultaneously, WNT, RAS/MAPK and PI3K/AKT activity and/or expression are affected and may impact on the sensitivity and the intensity of HIF-2?-regulated pathways. Furthermore, genes coding the identified HIF-2?-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.