Research Papers:

This article has been corrected. Correction in: Oncotarget. 2017; 8:36931.

PDGFRα depletion attenuates glioblastoma stem cells features by modulation of STAT3, RB1 and multiple oncogenic signals

Carlo Cenciarelli _, Hany E. Marei, Armando Felsani, Patrizia Casalbore, Gigliola Sica, Maria Ausiliatrice Puglisi, Angus JM Cameron, Alessandro Olivi and Annunziato Mangiola

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Oncotarget. 2016; 7:53047-53063. https://doi.org/10.18632/oncotarget.10132

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Carlo Cenciarelli1, Hany E. Marei2, Armando Felsani3, Patrizia Casalbore3, Gigliola Sica4, Maria Ausiliatrice Puglisi5, Angus J.M. Cameron6, Alessandro Olivi7, Annunziato Mangiola7

1Institute of Translational Pharmacology, Department of Biomedical Sciences-National Research Council (IFT-CNR), Rome, Italy

2Biomedical Research Center, Qatar University, Doha, Qatar

3Institute of Cell Biology and Neurobiology, Dept. of Biomedical Sciences-National Research Council (IBCN-CNR), Rome, Italy

4Institute of Histology and Embryology, Catholic University-School of Medicine, Rome, Italy

5Department of Internal Medicine and Gastroenterology, Agostino Gemelli Hospital, Rome, Italy

6Barts Cancer Institute, John Vane Science Centre, Queen Mary University of London, London, United Kingdom

7Institute of Neurosurgery, Department of Head and Neck, Catholic University-School of Medicine, Rome, Italy

Correspondence to:

Carlo Cenciarelli, email: carlo.cenciarelli@ift.cnr.it

Keywords: glioblastoma, cancer stem cells, PDGFRα, STAT3, RB1

Received: April 05, 2016     Accepted: June 09, 2016     Published: June 17, 2016


Platelet derived growth factor receptors (PDGFRs) play an important role in tumor pathogenesis, and they are frequently overexpressed in glioblastoma (GBM). Earlier we have shown a higher protein expression of PDGFR isoforms (α and β) in peritumoral-tissue derived cancer stem cells (p-CSC) than in tumor core (c-CSC) of several GBM affected patients. In the current study, in order to assess the activity of PDGFRα/PDGF-AA signaling axis, we performed time course experiments to monitor the effects of exogenous PDGF-AA on the expression of downstream target genes in c-CSC vs p-CSC. Interestingly, in p-CSC we detected the upregulation of Y705-phosphorylated Stat3, concurrent with a decrement of Rb1 protein in its active state, within minutes of PDGF-AA addition. This finding prompted us to elucidate the role of PDGFRα in self-renewal, invasion and differentiation in p-CSC by using short hairpin RNA depletion of PDGFRα expression. Notably, in PDGFRα-depleted cells, protein analysis revealed attenuation of stemness-related and glial markers expression, alongside early activation of the neuronal marker MAP2a/b that correlated with the induction of tumor suppressor Rb1. The in vitro reduction of the invasive capacity of PDGFRα-depleted CSC as compared to parental cells correlated with the downmodulation of markers of epithelial-mesenchymal transition phenotype and angiogenesis. Surprisingly, we observed the induction of anti-apoptotic proteins and compensatory oncogenic signals such as EDN1, EDNRB, PRKCB1, PDGF-C and PDGF-D. To conclude, we hypothesize that the newly discovered PDGFRα/Stat3/Rb1 regulatory axis might represent a potential therapeutic target for GBM treatment.

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