Chitinase-3 like-protein-1 promotes glioma progression via the NF-κB signaling pathway and tumor microenvironment reprogramming

Abstract

Background: Chitinase-3-like protein 1 (CHI3L1) is overexpressed in various types of tumors, especially in glioma, and contributes to tumor progression. However, the definite role of CHI3L1 and involved pathway in glioma progression are not completely understood. Methods: CHI3L1 expression in human gliomas and its association with patient survival was determined using enzyme-linked immunosorbent assay, western blot, immunohistochemistry, and public databases. Single-cell RNA-seq was used to characterize the landscape of tumor and myeloid cells. Human proteome microarray assay was applied to identify the binding partners of CHI3L1. Protein-protein interactions were analyzed by co-immunoprecipitation and cellular co-localization. The roles of CHI3L1 in glioma proliferation and invasion were investigated in tumor cell lines by gain- and loss- of function, as well as in vivo animal experiments. Results: CHI3L1 was up-regulated in all disease stages of glioma, which was closely related with tumor survival, growth, and invasion. CHI3L1 was primarily expressed in glioma cells, followed by neutrophils. Moreover, glioma cells with high expression of CHI3L1 were significantly enriched in NF-κB pathway. Pseudo-time trajectory analysis revealed a gradual transition from CHI3L1 low to CHI3L1 high glioma cells, along with the NF-κB pathway gradually reversed from inhibition to activation. Intriguingly, CHI3L1 binds to actinin alpha 4 (ACTN4) and NFKB1, and enhances the NF-κB signaling pathway by promoting the NF-κB subunit nuclear translocation in glioma cells. Further, CHI3L1 were released into the tumor microenvironment (TME) and interacted with CD44 expressed on tumor-associated macrophages to activate AKT pathway, thereby contributing to M2 macrophage polarization. In addition, CHI3L1 positively correlated to the expression of immune checkpoints, such as CD274 (PD-L1) and HAVCR2 (LAG3), which then remodeled the TME to an immunosuppressive phenotype. Conclusion: Our research revealed that CHI3L1 facilitated NF-κB pathway activation within glioma cells and reprogramed the TME, thereby serving as a promising therapeutic target for glioma.

The Importance of M1-and M2-Polarized Macrophages in Glioma and as Potential Treatment Targets

“…Chitinase-3-like protein-1 (CHI3L1), known as human homolog YKL-40, belonging to the glycoside hydrolase family, is highly expressed in various tumors, especially in GBM, and is involved in extracellular tissue remodeling, Th1/Th2 inflammation, oxidative injury, apoptosis, pyroptosis, angiogenesis, and parenchymal scarring [ 153 , 154 , 155 ]. CHI3L1 is highly expressed in glioblastoma and is related to poor patient prognosis.…”

Hypoxia‐related THBD+ macrophages as a prognostic factor in glioma: Construction of a powerful risk model

“…and NFKB. 58 CHI3L1 is released into the TME, interacts with CD44 expressed on tumour-associated macrophages, and activates the AKT pathway, thus promoting polarization of M2 macrophages. Genes like TMEM140 and GPX8 also play regulatory roles in gliomas.…”

“… 57 Furthermore, the highly expressed CHI3L1 in gliomas enhances NF‐κB signalling by facilitating the translocation of NF‐κB subunits through binding to ACTN4 and NFKB. 58 CHI3L1 is released into the TME, interacts with CD44 expressed on tumour‐associated macrophages, and activates the AKT pathway, thus promoting polarization of M2 macrophages. Genes like TMEM140 and GPX8 also play regulatory roles in gliomas.…”

“…Additionally, upregulated STEAP3 in gliomas facilitates tumour cell migration and invasion and is significantly associated with immune‐infiltrating cells, including macrophages and neutrophils, particularly M2 macrophages 57 . Furthermore, the highly expressed CHI3L1 in gliomas enhances NF‐κB signalling by facilitating the translocation of NF‐κB subunits through binding to ACTN4 and NFKB 58 . CHI3L1 is released into the TME, interacts with CD44 expressed on tumour‐associated macrophages, and activates the AKT pathway, thus promoting polarization of M2 macrophages.…”

Long non-coding RNA LOXL1-AS1: a potential biomarker and therapeutic target in human malignant tumors

“…Therefore, it is critical to investigate new prognostic indicators for glioma and identify other targets for treating this deadly disease. Studies have shown that nuclear factor κB (NF-κB) signaling pathway plays an important role in the development of glioma by mediating inflammation and immune response [ 58 ]. Silencing LOXL1-AS1 inhibit glioma cell proliferation and participate in regulating the NF-κB signaling pathway by inhibiting RELB directly [ 59 ].…”