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// Giovanna Casili 1 , Maria Caffo 2 , Michela Campolo 1 , Valeria Barresi 3 , Gerardo Caruso 2 , Salvatore M. Cardali 2 , Marika Lanza 1 , Raffaella Mallamace 4 , Alessia Filippone 1 , Alfredo Conti 2 , Antonino Germano 2 , Salvatore Cuzzocrea 1 and Emanuela Esposito 1 1 Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina, Italy 2 Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Unit of Neurosurgery, University of Messina, Messina, Italy 3 Department of Human Pathology, University of Messina, Messina, Italy 4 Unit of Anesthesia, University of Messina, Messina, Italy Correspondence to: Emanuela Esposito, email: eesposito@unime.it Keywords: glioblastomas; TLR-4; Wnt; Dkk-3; claudin-5 Received: February 19, 2018 Accepted: December 13, 2018 Published: December 25, 2018 ABSTRACT Purpose: Glioblastomas are highly aggressive brain tumors. Various pathways are involved in gliomagenesis, among which the Wingless (Wnt) signaling. Dickkopf protein-related protein 3 (Dkk-3) interacts with proteins of Wnt pathwayas inhibitor. The Wnt signaling contributes to activity of the claudins, that are critical components of tight junctions, whose expression was altered selectively in cerebral microvessels of glioblastoma. The aim of this study was to determine the role of Wnt pathways in the regulation of tumor growth, apoptosis process by targeting Dkk-3, tight junctions alteration involving claudin-5, suggesting possible therapeutic interactions involving Wnt/Toll-like receptors (TLRs) pathways. Results: We showed a significant decreasing of Dkk-3 and claudin-5 in human glioblastoma cell lines, as well as in U-87 MG xenograft tumors and in glioblastoma human patient’s tissues, with an involvement of the apoptosis process. Also, an interesting TLR-4/Wnt modulation highlighted that the absence of TLR-4 determined resistance to the tumor onset. Conclusions: We concluded that combined modulation of Wnt/Dkk-3/claudin-5 and TLR-4 pathways, simultaneously targeting apoptosis and survival signaling defects, might shift the balance from tumor growth stasis to cytotoxic therapeutic responses, flowing in greater therapeutic benefits. Methods: In the present study we investigated the expression of Dkk-3, claudin-5, apoptosis markers and TLR-4 receptor protein levels in in vitro studies on U-138MG, A-172, LN-18 and LN-229 human glioblastoma cell lines, and in vivo study using TLR-4 KO mice and in glioblastoma human patient’s tissues.