title: A unique four-hub protein cluster associates to glioblastoma progression.
abstract: Gliomas are the most frequent brain tumors. Among them, glioblastomas are malignant and largely resistant to available treatments. Histopathology is the gold standard for classification and grading of brain tumors. However, brain tumor heterogeneity is remarkable and histopathology procedures for glioma classification remain unsatisfactory for predicting disease course as well as response to treatment. Proteins that tightly associate with cancer differentiation and progression, can bear important prognostic information. Here, we describe the identification of protein clusters differentially expressed in high-grade versus low-grade gliomas. Tissue samples from 25 high-grade tumors, 10 low-grade tumors and 5 normal brain cortices were analyzed by 2D-PAGE and proteomic profiling by mass spectrometry. This led to identify 48 differentially expressed protein markers between tumors and normal samples. Protein clustering by multivariate analyses (PCA and PLS-DA) provided discrimination between pathological samples to an unprecedented extent, and revealed a unique network of deranged proteins. We discovered a novel glioblastoma control module centered on four major network hubs: Huntingtin, HNF4α, c-Myc and 14-3-3ζ. Immunohistochemistry, western blotting and unbiased proteome-wide meta-analysis revealed altered expression of this glioblastoma control module in human glioma samples as compared with normal controls. Moreover, the four-hub network was found to cross-talk with both p53 and EGFR pathways. In summary, the findings of this study indicate the existence of a unifying signaling module controlling glioblastoma pathogenesis and malignant progression, and suggest novel targets for development of diagnostic and therapeutic procedures.
authors: Unit of Cancer Pathology, Ce.S.I., Foundation University "G. d'Annunzio," Chieti, Italy.
authors: Pasquale
authors: P
authors: Simeone
authors: Unit of Cancer Pathology, Ce.S.I., Foundation University "G. d'Annunzio," Chieti, Italy.
authors: Marco
authors: M
authors: Trerotola
authors: Unit of Cancer Pathology, Ce.S.I., Foundation University "G. d'Annunzio," Chieti, Italy.
authors: Andrea
authors: A
authors: Urbanella
authors: Unit of Cancer Pathology, Ce.S.I., Foundation University "G. d'Annunzio," Chieti, Italy; Department of Experimental and Clinical Sciences, School of Medicine and Health Science, University "G. d'Annunzio," Chieti, Italy.
authors: Rossano
authors: R
authors: Lattanzio
authors: School of Human and Social Science, University "Kore" of Enna, Enna, Italy; Molecular Neurology Unit, Ce.S.I., University "G. d'Annunzio," Chieti, Italy.
authors: Domenico
authors: D
authors: Ciavardelli
authors: Aging Research Center, Ce.S.I., University "G. d'Annunzio" Foundation, Chieti, Italy; Department of Experimental and Clinical Sciences, School of Medicine and Health Science, University "G. d'Annunzio," Chieti, Italy; StemTeCh Group, Chieti, Italy.
authors: Fabrizio
authors: F
authors: Di Giuseppe
authors: Aging Research Center, Ce.S.I., University "G. d'Annunzio" Foundation, Chieti, Italy; Department of Experimental and Clinical Sciences, School of Medicine and Health Science, University "G. d'Annunzio," Chieti, Italy; StemTeCh Group, Chieti, Italy.
authors: Enrica
authors: E
authors: Eleuterio
authors: Aging Research Center, Ce.S.I., University "G. d'Annunzio" Foundation, Chieti, Italy; Department of Experimental and Clinical Sciences, School of Medicine and Health Science, University "G. d'Annunzio," Chieti, Italy; StemTeCh Group, Chieti, Italy.
authors: Marilisa
authors: M
authors: Sulpizio
authors: Department of "Tutela Salute Donna, Vita nascente, Bambino e Adolescente," Catholic University of the Sacred Heart, Policlinico Universitario "Agostino Gemelli," Roma, Italy.
authors: Vincenzo
authors: V
authors: Eusebi
authors: Section of Surgical Pathology, "M. Malpighi," Bellaria Hospital, Bologna, Italy.
authors: Annalisa
authors: A
authors: Pession
authors: Unit of Cancer Pathology, Ce.S.I., Foundation University "G. d'Annunzio," Chieti, Italy; Department of Experimental and Clinical Sciences, School of Medicine and Health Science, University "G. d'Annunzio," Chieti, Italy.
authors: Mauro
authors: M
authors: Piantelli
authors: Unit of Cancer Pathology, Ce.S.I., Foundation University "G. d'Annunzio," Chieti, Italy; Department of Neuroscience, Imaging and Clinical Sciences, University "G. d'Annunzio," Chieti, Italy.
authors: Saverio
authors: S
authors: Alberti
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D016000:Cluster Analysis; D015180:Electrophoresis, Gel, Two-Dimensional; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D013058:Mass Spectrometry; D015999:Multivariate Analysis; D060066:Protein Interaction Maps; D020543:Proteome / Q000032:analysis* / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D015398:Signal Transduction
chemical_list: D014408:Biomarkers, Tumor; D020543:Proteome