Cellular prion protein controls stem cell-like properties of human glioblastoma tumor-initiating cells
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Alessandro Corsaro1, Adriana Bajetto1, Stefano Thellung1,2, Giulia Begani1, Valentina Villa1, Mario Nizzari1, Alessandra Pattarozzi1, Agnese Solari1, Monica Gatti1, Aldo Pagano3,4, Roberto Würth1, Antonio Daga4, Federica Barbieri1,2, Tullio Florio1,2
1Sezione di Farmacologia, Dipartimento di Medicina Interna, University of Genova, Genova, Italy
2Centro di Eccellenza per la Ricerca Biomedica (CEBR), University of Genova, Genova, Italy
3Department of Experimental Medicine, University of Genova, Genova, Italy
4IRCCS AOU San Martino - IST, Genova, Italy
Tullio Florio, email: [email protected]
Keywords: prion protein, glioblastoma, cancer stem cells, in vivo tumorigenicity, GFAP
Received: December 30, 2015 Accepted: May 04, 2016 Published: May 24, 2016
Prion protein (PrPC) is a cell surface glycoprotein whose misfolding is responsible for prion diseases. Although its physiological role is not completely defined, several lines of evidence propose that PrPC is involved in self-renewal, pluripotency gene expression, proliferation and differentiation of neural stem cells. Moreover, PrPC regulates different biological functions in human tumors, including glioblastoma (GBM). We analyzed the role of PrPC in GBM cell pathogenicity focusing on tumor-initiating cells (TICs, or cancer stem cells, CSCs), the subpopulation responsible for development, progression and recurrence of most malignancies. Analyzing four GBM CSC-enriched cultures, we show that PrPC expression is directly correlated with the proliferation rate of the cells. To better define its role in CSC biology, we knocked-down PrPC expression in two of these GBM-derived CSC cultures by specific lentiviral-delivered shRNAs. We provide evidence that CSC proliferation rate, spherogenesis and in vivo tumorigenicity are significantly inhibited in PrPC down-regulated cells. Moreover, PrPC down-regulation caused loss of expression of the stemness and self-renewal markers (NANOG, Sox2) and the activation of differentiation pathways (i.e. increased GFAP expression). Our results suggest that PrPC controls the stemness properties of human GBM CSCs and that its down-regulation induces the acquisition of a more differentiated and less oncogenic phenotype.
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