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Inhibition of CHI3L1 decreases N-cadherin and VCAM-1 levels in glioblastoma
Agnieszka Rusak1, Marlena Gąsior-Głogowska2, Azzurra Sargenti3
1Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, T. Chalubinskiego St. 6a, 50-368 Wroclaw, Poland.
Background:
(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.
Methods:
(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.
Results:
(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.
Conclusion:
(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.
Insights
Chitinase-3-like protein 1 (CHI3L1) inhibition reduces glioblastoma multiforme (GBM) invasiveness. This study utilized 3D GBM spheroids to investigate CHI3L1
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Chitinase-3-like protein 1 (CHI3L1) promotes cancer progression via angiogenesis, invasion, and immunomodulation.
- CHI3L1 is highly expressed in glioblastoma multiforme (GBM), a highly angiogenic cancer.
- Targeting CHI3L1 offers potential for precision medicine in GBM treatment.
Purpose of the Study:
- To investigate the effect of CHI3L1 inhibition on GBM invasiveness using a 3D spheroid model.
- To analyze the interaction between CHI3L1 and the inhibitor G721-0282.
- To assess changes in key molecular markers associated with GBM invasion.
Main Methods:
- Molecular docking and infrared spectroscopy to analyze CHI3L1 and G721-0282 interaction.
- Label-free physical cytometry to measure inhibitor uptake in GBM spheroids.
- Immunohistochemistry, Western blot, and ddPCR to analyze cadherins, VCAM-1, and EGFR expression.
Main Results:
- Direct interaction confirmed between CHI3L1 and G721-0282.
- G721-0282 significantly decreased N-cadherins and VCAM-1 in 3D GBM spheroids.
- Observed differential effects of G721-0282 on U-87 MG cells in 2D vs. 3D models.
Conclusions:
- CHI3L1 inhibition demonstrates potential in reducing GBM tumor invasiveness.
- The 3D GBM spheroid model is valuable for studying tumor microenvironment and membrane protein alterations.
- Further research into CHI3L1 inhibition could lead to novel GBM therapies.
