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Intermittent Hypoxia Regulates Stem-like Characteristics and Differentiation of Neuroblastoma Cells

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Title: Intermittent Hypoxia Regulates Stem-like Characteristics and Differentiation of Neuroblastoma Cells
Author(s): Bhaskara, Vasantha Kumar; Mohanam, Indra; Rao, Jasti S.; Mohanam, Sanjeeva
Abstract: Background: Neuroblastomas are the most common extracranial solid tumors in children. Neuroblastomas are derived from immature cells of the sympathetic nervous system and are characterized by clinical and biological heterogeneity. Hypoxia has been linked to tumor progression and increased malignancy. Intermittent hypoxia or repeated episodes of hypoxia followed by re-oxygenation is a common phenomenon in solid tumors including neuroblastoma and it has a significant influence on the outcome of therapies. The present study focuses on how intermittent hypoxia modulates the stem-like properties and differentiation in neuroblastoma cells. Methods and Findings: Cell survival was assessed by clonogenic assay and cell differentiation was determined by morphological characterization. Hypoxia-inducible genes were analyzed by real-time PCR and Western blotting. Immunofluorescence, real-time PCR and Western blotting were utilized to study stem cell markers. Analysis of neural crest / sympathetic nervous system (SNS) markers and neuronal differentiation markers were done by real-time PCR and Western blotting, respectively. Intermittent hypoxia stimulated the levels of HIF-1a and HIF-2 a proteins and enhanced stem-like properties of neuroblastoma cells. In intermittent hypoxia-conditioned cells, downregulation of SNS marker genes and upregulation of genes expressed in the neural crest were observed. Intermittent hypoxia suppressed the retinoic acidinduced differentiation of neuroblastoma cells. Conclusions: Our results suggest that intermittent hypoxia enhances stem-like characteristics and suppresses ifferentiation propensities in neuroblastoma cells.
Issue Date: 2012-02
Publisher: Public Library of Science
Citation Info: Bhaskara, V. K., Mohanam, I., Rao, J. S., & Mohanam, S. 2012. Intermittent Hypoxia Regulates Stem-like Characteristics and Differentiation of Neuroblastoma Cells. PLoS One, 7(2): e30905. doi:10.1371/journal.pone.0030905
Type: Article
Description: © 2012 Bhaskara et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. doi:10.1371/journal.pone.0030905
ISSN: 1932-6203
Sponsor: This research was supported by a grant from the National Cancer Institute CA138466 to SM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Date Available in INDIGO: 2012-08-16

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