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Overexpression of Macrophage Migration Inhibitory Factor and Its Homologue D-Dopachrome Tautomerase as Negative Prognostic Factor in Neuroblastoma

IRCCS Centro Neurolesi Bonino Pulejo, C.da Casazza, 98124 Messina, Italy
Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
Author to whom correspondence should be addressed.
Brain Sci. 2019, 9(10), 284;
Received: 27 August 2019 / Revised: 1 October 2019 / Accepted: 18 October 2019 / Published: 19 October 2019
(This article belongs to the Section Developmental Neuroscience)
Neuroblastoma (NB) represents one of the most frequent pediatric solid tumors. Macrophage migration inhibitory factor (MIF) is a cytokine exerting multiple biological functions. More recently, a second member of the MIF family of cytokine has been identified, the D-dopachrome tautomerase (DDT), that exerts several overlapping functions with MIF. Growing evidence suggests a key role for MIF and DDT in the development of cancer. The aim of this study is to characterize the prognostic value of MIF and DDT in NB. We show that higher expression levels of MIF and DDT in Stage 4 NB samples are associated with a poorer prognosis, independently of the presence of MYCN amplification. Moreover, higher levels of MIF are mostly enriched by Th1 cells, while lower levels of MIF are associated with an increased proportion of B cells, Cytotoxic T cells, Dendritic cells and Natural Killer T cells. We also show that treatment with the histone deacetylase (HDAC) inhibitor, vorinostat, of the NB cell line, SH-SY5Y, determines a significant reduction in the expression of both MIF and DDT. Finally, MIF and DDT inhibition by short interfering RNA is able to revert vincristine sensitivity in vitro. Overall, our data suggest that MIF exert pro-tumorigenic properties in NB, likely by dampening antigen presentation and cytotoxic immune responses, and we propose the HDAC inhibitors as a potential therapeutic strategy for NB patients. View Full-Text
Keywords: Neuroblastoma; MIF; DDT Neuroblastoma; MIF; DDT
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Cavalli, E.; Mazzon, E.; Mammana, S.; Basile, M.S.; Lombardo, S.D.; Mangano, K.; Bramanti, P.; Nicoletti, F.; Fagone, P.; Petralia, M.C. Overexpression of Macrophage Migration Inhibitory Factor and Its Homologue D-Dopachrome Tautomerase as Negative Prognostic Factor in Neuroblastoma. Brain Sci. 2019, 9, 284.

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