Hypoxia-Inducible Factor-1α (HIF-1α) Inhibition Impairs Retinoic Acid-Induced Differentiation in SH-SY5Y Neuroblastoma Cells, Leading to Reduced Neurite Length and Diminished Gene Expression Related to Cell Differentiation

• DOI: 10.1007/s11064-021-03454-3
• Publication Date: 2021-09-24T02:47:13Z
• Authors: Pedro Ozorio Brum; Guilherme Daniels...; Carolina Saibro-G...; Camila Tiefensee-...; Matheus Ozorio Brum; Juciano Gasparotto; Rachel Krolow; José Cláudio Fons...; Daniel Pens Gelain
• Keywords: 0301 basic medicine; Original Paper; 0303 health sciences; HIF-1; Gene Expression; Cell Differentiation; Tretinoin; SH-SY5Y; Hypoxia-Inducible Factor 1, alpha Subunit; 3. Good health; Neuroblastoma; 03 medical and health sciences; Differentiation; Cell Line, Tumor; Neurites; Humans; Hypoxia; Cancer

AbstractNeuroblastoma is the most common extracranial solid tumour in childhood, originated from cells of the neural crest during the development of the Sympathetic Nervous System. Retinoids are vitamin-A derived differentiating agents utilised to avoid disease resurgence in high-risk neuroblastoma treatment. Several studies indicate that hypoxia—a common feature of the tumoural environment—is a key player in cell differentiation and proliferation. Hypoxia leads to the accumulation of the hypoxia-inducible factor-1α (HIF-1α). This work aims to investigate the effects of the selective inhibition of HIF-1α on the differentiation induced by retinoic acid in human neuroblastoma cells from the SH-SY5Y lineage to clarify its role in cell differentiation. Our results indicate that HIF-1α inhibition impairs RA-induced differentiation by reducing neuron-like phenotype and diminished immunolabeling and expression of differentiation markers. Graphic Abstract

HIF1A is involved in Retinoic Acid (RA) induced differentiation in SH-SY5Y neuroblastoma cells. siRNA HIF1A gene silencing leads to a weaker response to RA, demonstrated by changes in the neuro-like phenotype and diminished expression of differentiation markers.