Chitinase-3 like-protein-1 function and its role in diseases

Abstract

Non-enzymatic chitinase-3 like-protein-1 (CHI3L1) belongs to glycoside hydrolase family 18. It binds to chitin, heparin, and hyaluronic acid, and is regulated by extracellular matrix changes, cytokines, growth factors, drugs, and stress. CHI3L1 is synthesized and secreted by a multitude of cells including macrophages, neutrophils, synoviocytes, chondrocytes, fibroblast-like cells, smooth muscle cells, and tumor cells. It plays a major role in tissue injury, inflammation, tissue repair, and remodeling responses. CHI3L1 has been strongly associated with diseases including asthma, arthritis, sepsis, diabetes, liver fibrosis, and coronary artery disease. Moreover, following its initial identification in the culture supernatant of the MG63 osteosarcoma cell line, CHI3L1 has been shown to be overexpressed in a wealth of both human cancers and animal tumor models. To date, interleukin-13 receptor subunit alpha-2, transmembrane protein 219, galectin-3, chemo-attractant receptor-homologous 2, and CD44 have been identified as CHI3L1 receptors. CHI3L1 signaling plays a critical role in cancer cell growth, proliferation, invasion, metastasis, angiogenesis, activation of tumor-associated macrophages, and Th2 polarization of CD4⁺ T cells. Interestingly, CHI3L1-based targeted therapy has been increasingly applied to the treatment of tumors including glioma and colon cancer as well as rheumatoid arthritis. This review summarizes the potential roles and mechanisms of CHI3L1 in oncogenesis and disease pathogenesis, then posits investigational strategies for targeted therapies.

Fig. 1

Crystal structure, source, and expression regulation of CHI3L1. a A long carbohydrate-binding cleft is present at the C-terminal side of the beta-strands. Binding of chitotetraose is shown in the groove. b CHI3L1 is synthesized and secreted by a multitude of cells. CHI3L1 expression is regulated by miRNAs, cytokines, growth factors (GF), drugs, and stress. SMC smooth muscle cell, FLC fibroblast like cells, HSC hepatic stellate cell

Fig. 2

CHI3L1 interacts with IL-13-IL-13Rα2 to form a multimeric complex, and synergistically interacts with TMEM219 and Gal-3, respectively. CHI3L1 binds IL-13Rα2 to activate the Erk, Akt, and Wnt/β-catenin pathways to regulate apoptosis, pyroptosis, inflammasome activation, antibacterial responses, and malignancy metastasis. The binding ability of IL-13 with IL-13Rα2 is increased in the presence of TMEM219, thereby enhancing the anti-apoptosis response induced by CHI3L1 stimulation. Gal-3 interacts with CHI3L1–IL-13-IL-13Rα2 complex to compete with TMEM219 for IL-13Rα2 binding to diminish the anti-apoptotic role of CHI3L1. HPS Hermansky–Pudlak syndrome, HB-EGF heparin-binding EGF-like growth factor

Fig. 3

CHI3L1 physically interacts with the CD44 to promote GC invasion and metastasis. CHI3L1 is highly expressed in GC tissues and patient sera, and interacts with CD44v3 to activate the Akt, Erk, and β-catenin signaling pathways, contributing to GC progression

Fig. 4

CHI3L1 induces angiogenesis and cancer cell proliferation to facilitate glioblastoma progression. CHI3L1 binds the HS chain of Syn-1 to induce coordination between Syn-1 and the integrin α_vβ₃, triggering the FAK⁸⁶¹ and MAPK/Erk1/2 and PI3K signaling pathways to produce the endothelial cell angiogenic signature. Similarly, CHI3L1 induces coordination between Syn-1 and integrin α_vβ₅ to activate FAK³⁹⁷ and downstream signaling pathways, upregulating VEGF. Interestingly, sustained inhibition of VEGF finally upregulates CHI3L1 expression, which contributes to anti-VEGF resistance and invasiveness

Fig. 5

CHI3L1 is overexpressed in certain cancer types. The level of CHI3L1 is significantly overexpressed in tumors including BLCA, COAD, GBM, OV, PAAD, READ, STAD, THCA, and UCEC. However, it is downregulated in BRCA, and shows no difference among LIHC and LUAD (from http://gepia.cancer-pku.cn). *p<0.05. BLCA bladder urothelial carcinoma, BRCA breast invasive carcinoma, COAD colon adenocarcinoma, GBM glioblastoma multiforme, LIHC liver hepatocellular carcinoma, LUAD lung adenocarcinoma, OV ovarian serous cystadenocarcinoma, PAAD pancreatic adenocarcinoma, READ rectum adenocarcinoma, STAD stomach adenocarcinoma, THCA thyroid carcinoma, UCEC uterine corpus endometrial carcinoma

Fig. 6

Elevated expression CHI3L1 is inversely correlated with the survival of patients with malignancy. CHI3L1 is overexpressed in patients with breast cancer, bladder carcinoma, lung squamous cell carcinoma, ovarian cancer, gastric cancer, and glioma, and is associated with lower survival rates. Conversely, no relationship is found between CHI3L1 overexpression and survival in patients with cervical squamous cell carcinoma and liver cancer, while a negative correlation was observed between among patients bearing sarcoma. (from https://kmplot.com, http://www.cgga.org.cn)

Fig. 7

Possible effects of CHI3L1 on liver fibrosis