PATZ1 is a new prognostic marker of glioblastoma associated with the stem-like phenotype and enriched in the proneural subtype

// Elia Guadagno 1 , Michela Vitiello 2 , Paola Francesca 2 , Gaetano Cali 2 , Federica Caponnetto 3 , Daniela Cesselli 3 , Simona Camorani 2 , Giorgio Borrelli 1 , Marialuisa Califano 1 , Paolo Cappabianca 4 , Claudio Arra 5 , Elvira Crescenzi 2 , Laura Cerchia 2 , Maria Laura Del Basso De Caro 1 and Monica Fedele 2 1 Department of Advanced Biomedical Sciences, Pathology Section, University of Naples Federico II, 80131 Naples, Italy 2 Institute of Experimental Endocrinology and Oncology (IEOS) “Gaetano Salvatore”, National Council of Research, 80131 Naples, Italy 3 Department of Medical and Biological Sciences, University of Udine, 33100 Udine, Italy 4 Division of Neurosurgery, Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples Federico II, 80131 Naples, Italy 5 Department of Experimental Oncology, National Cancer Institute “Fondazione Giovanni Pascale”, IRCCS, 80131 Naples, Italy Correspondence to: Monica Fedele, email: mfedele@unina.it , monica.fedele@cnr.it Maria Laura Del Basso De Caro, email: marialaura.delbasso@unina.it Keywords: glioma, glioma stem cells, PATZ1, tumor heterogeneity, biomarker Received: January 18, 2017     Accepted: June 19, 2017     Published: July 25, 2017 ABSTRACT Glioblastoma (GBM), the most malignant of the brain tumors, has been classified on the basis of molecular signature into four subtypes: classical, mesenchymal, proneural and neural, among which the mesenchymal and proneural subtypes have the shortest and longest survival, respectively. Here we show that the transcription factor PATZ1 gene is upregulated in gliomas compared to normal brain and, among GBMs, is particularly enriched in the proneural subtype and co-localize with stemness markers. Accordingly, in GBM-derived glioma-initiating stem cells (GSCs) PATZ1 is overexpressed compared to differentiated tumor cells and its expression significantly correlates with the characteristic stem cell capacity to grow as neurospheres in vitro . Interestingly, survival analysis demonstrated that PATZ1 lower levels informed poor prognosis in GBM and, specifically, in the proneural subgroup, suggesting it may serve a role as diagnostic and prognostic biomarker for intra-subtype heterogeneity of proneural GBM. We also show that PATZ1 suppresses the expression of the mesenchyme-inducer CXCR4, and that PATZ1 and CXCR4 are inversely correlated in GSC and proneural GBM. Overall these findings support a central role of PATZ1 in regulating malignancy of GBM.