title: The emerging role of GSK-3β in the pathobiology of classical Hodgkin lymphoma.
abstract: OBJECTIVE
  Glycogen synthase kinase-3 beta (GSK-3β) is a serine/threonine kinase involved in glycogen metabolism, cell cycle progression, differentiation, embryogenesis, migration, metabolism, survival and cellular senescence. Its main biological function is to inhibit β-catenin by sequestration and promotion of its proteasomal degradation in the Wnt canonical pathway; however, GSK-3β interacts with multiple signalling pathways, and aberrant expression of the enzyme was reported in many solid neoplasms. This study aimed to investigate the biological relevance of GSK-3β in classical Hodgkin lymphomas (cHL).
  
  
  RESULTS
  We analysed the functional status of GSK-3β enzyme in cHL by using antibodies raised against fixation-resistant epitopes of phospho Y216 GSK-3β (active form), phospho S9 GSK-3β (inactive form) and β-catenin protein. We first detected the pY216 GSK-3β active form of the enzyme in 100 of 100 (100%) of the cases, and in line with the latter expression profile, the β-catenin protein was found in only 12 of 100 (12%) of the samples. As reported previously in bladder cancer, pancreatic adenocarcinoma and chronic lymphocytic leukaemia, we showed an aberrant nuclear localization in the neoplastic clone of active pY216 GSK-3β in 78 of 100 (78%) of cHL cases.
  
  
  CONCLUSIONS
  We demonstrated the activation of GSK-3β in cHL resulting in inhibition of the Wnt/β-catenin signal cascade and the aberrant accumulation of its activated form in nuclei of Hodgkin Reed-Sternberg and Hodgkin cells. These findings may be relevant for future clinical studies, identifying GSK-3β as a potential therapeutic target for cHL.
authors.affiliation: Hematopathology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology 'L. e A. Seragnoli', University of Bologna, Bologna, Italy.
authors.forename: Claudio
authors.identifier: http://orcid.org/0000-0002-4945-1422
authors.initials: C
authors.lastname: Agostinelli
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRCCS, Meldola, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Carloni
authors.affiliation: Hematopathology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology 'L. e A. Seragnoli', University of Bologna, Bologna, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Limarzi
authors.affiliation: Hematopathology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology 'L. e A. Seragnoli', University of Bologna, Bologna, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Righi
authors.affiliation: Hematopathology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology 'L. e A. Seragnoli', University of Bologna, Bologna, Italy.
authors.forename: Maria Antonella
authors.initials: MA
authors.lastname: Laginestra
authors.affiliation: Hematology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRCCS, Meldola, Italy.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Musuraca
authors.affiliation: Pathology Service, Addarii Institute of Oncology, S-Orsola-Malpighi Hospital, Bologna, Italy.
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Fiorentino
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRCCS, Meldola, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Napolitano
authors.affiliation: Department of Medical Sciences, University of Ferrara-Arcispedale Sant'Anna, Ferrara, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cuneo
authors.affiliation: Laboratory of Clinical Proteomic, 'Giovanni Paolo II' Hospital, ASL-Lecce, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Vergara
authors.affiliation: Hemathology Section, Department of Experimental, Diagnostic and Specialty Medicine, Bologna University School of Medicine, Bologna, Italy.
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Zinzani
authors.affiliation: Hematopathology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology 'L. e A. Seragnoli', University of Bologna, Bologna, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Sabattini
authors.affiliation: Professor Alma Mater Bologna University, Bologna, Italy.|Hematopathology Unit, European Institute of Oncology, Milan, Italy.
authors.forename: Stefano A
authors.initials: SA
authors.lastname: Pileri
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRCCS, Meldola, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: De Matteis
mesh_terms: D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D006689:Hodgkin Disease / Q000378:metabolism*; D006801:Humans; D059467:Transcriptome
chemical_list: D000071679:Glycogen Synthase Kinase 3 beta
keywords: GSK-3β; Hodgkin; β-catenin