title: Cellular prion protein controls stem cell-like properties of human glioblastoma tumor-initiating cells.
abstract: 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.
authors.affiliation: Sezione di Farmacologia, Dipartimento di Medicina Interna, University of Genova, Genova, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Corsaro
authors.affiliation: Sezione di Farmacologia, Dipartimento di Medicina Interna, University of Genova, Genova, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Bajetto
authors.affiliation: Sezione di Farmacologia, Dipartimento di Medicina Interna, University of Genova, Genova, Italy.|Centro di Eccellenza per la Ricerca Biomedica (CEBR), University of Genova, Genova, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Thellung
authors.affiliation: Sezione di Farmacologia, Dipartimento di Medicina Interna, University of Genova, Genova, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Begani
authors.affiliation: Sezione di Farmacologia, Dipartimento di Medicina Interna, University of Genova, Genova, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Villa
authors.affiliation: Sezione di Farmacologia, Dipartimento di Medicina Interna, University of Genova, Genova, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Nizzari
authors.affiliation: Sezione di Farmacologia, Dipartimento di Medicina Interna, University of Genova, Genova, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pattarozzi
authors.affiliation: Sezione di Farmacologia, Dipartimento di Medicina Interna, University of Genova, Genova, Italy.
authors.forename: Agnese
authors.initials: A
authors.lastname: Solari
authors.affiliation: Sezione di Farmacologia, Dipartimento di Medicina Interna, University of Genova, Genova, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Gatti
authors.affiliation: Department of Experimental Medicine, University of Genova, Genova, Italy.|IRCCS AOU San Martino - IST, Genova, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Pagano
authors.affiliation: Sezione di Farmacologia, Dipartimento di Medicina Interna, University of Genova, Genova, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Würth
authors.affiliation: IRCCS AOU San Martino - IST, Genova, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Daga
authors.affiliation: Sezione di Farmacologia, Dipartimento di Medicina Interna, University of Genova, Genova, Italy.|Centro di Eccellenza per la Ricerca Biomedica (CEBR), University of Genova, Genova, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Barbieri
authors.affiliation: Sezione di Farmacologia, Dipartimento di Medicina Interna, University of Genova, Genova, Italy.|Centro di Eccellenza per la Ricerca Biomedica (CEBR), University of Genova, Genova, Italy.
authors.forename: Tullio
authors.initials: T
authors.lastname: Florio
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D000072002:Prion Proteins / Q000378:metabolism*; D014162:Transfection
chemical_list: D000072002:Prion Proteins
keywords: GFAP; cancer stem cells; glioblastoma; in vivo tumorigenicity; prion protein