Inhibition of CHI3L1 decreases N-cadherin and VCAM-1 levels in glioblastoma.

Abstract

(1)The protein CHI3L1 supports cancer development in several ways, including stimulation of angiogenesis and invasion as well as immunomodulatory effects. These properties make it a potential target for the development of targeted therapies in precision medicine. In this context, the particular potential of CHI3L1 inhibition could be considered in glioblastoma multiforme (GBM), whose tumors exhibit high levels of angiogenesis and increased CHI3L1 expression. This study aims to investigate whether inhibition of CHI3L1 in spheroids used as a GBM model affects the mechanisms of invasiveness. (2)We analyzed the interactions between CHI3L1 and the inhibitor G721-0282 in molecular docking (in silico) and infrared spectroscopy. Uptake of G721-0282 in GBM spheroids was measured using a label-free physical cytometer. Changes in E-, N- and VE-cadherins, VCAM-1 and EGFR were analyzed by immunohistochemical reactions, Western blot and ddPCR methods in U-87 MG cells and GBM spheroids consisting of U-87 MG glioblastoma cells, HMEC-1 endothelial cells and macrophages. (3)A direct interaction between CHI3L1 and G721-0282 was observed. G721-0282 decreased N-cadherins and VCAM-1 in GBM spheroids, but the changes in the 2D model of U-87 MG glioblastoma cells were different. (4)Inhibition of CHI3L1 has the potential to reduce the invasiveness of GBM tumors. The proposed 3D model of GBM spheroids is of great significance for investigating changes in membrane proteins and the tumor microenvironment.