The emerging role of GSK-3 beta in the pathobiology of classical Hodgkin lymphoma

作者：Agostinelli Claudio^*; Carloni Silvia; Limarzi Francesco; Righi Simona; Laginestra Maria Antonella; Musuraca Gerardo; Fiorentino Michelangelo; Napolitano Roberta; Cuneo Antonio; Vergara Daniele; Zinzani Pier Luigi; Sabattini Elena; Pileri Stefano A; De Matteis Serena

来源：Histopathology, 2017, 71(1): 72-80.

DOI：10.1111/his.13189

• GSK-3 beta
• Hodgkin
• beta-catenin

Aims: Glycogen synthase kinase-3 beta (GSK-3 beta) 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 beta-catenin by sequestration and promotion of its proteasomal degradation in the Wnt canonical pathway; however, GSK-3 beta 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-3 beta in classical Hodgkin lymphomas (cHL).
Methods and results: We analysed the functional status of GSK-3 beta enzyme in cHL by using antibodies raised against fixation-resistant epitopes of phospho Y216 GSK-3 beta (active form), phospho S9 GSK-3 beta (inactive form) and beta-catenin protein. We first detected the pY216 GSK-3 beta active form of the enzyme in 100 of 100 (100%) of the cases, and in line with the latter expression profile, the beta-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-3 beta in 78 of 100 (78%) of cHL cases.
Conclusions: We demonstrated the activation of GSK-3 beta in cHL resulting in inhibition of the Wnt/beta-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-3 beta as a potential therapeutic target for cHL.

• 出版日期2017-7