ISSN: 1838-7640Theranostics
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Theranostics 2022; 12(16):6989-7008. doi:10.7150/thno.75069 This issue Cite
Research Paper
Chitinase-3 like-protein-1 promotes glioma progression via the NF-κB signaling pathway and tumor microenvironment reprogramming
1. Affiliated Cancer Hospital & Institute, Guangzhou Medical University, Guangzhou 510095, Guangdong, China.
2. Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
3. Faculty of Health Sciences, University of Macau, Taipa, Macau, China.
4. Department of Biotherapy, Department of Geriatrics, Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, Jiangsu, China.
5. Department of Neurosurgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing 210008, Jiangsu, China.
6. Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China.
7. College of Life Science and Technology, Jinan University, 601 Huangpu Road, Guangzhou 510630, China.
8. Key Laboratory of Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes, Guangzhou Medical University, Guangzhou 510182, China.
9. Center for Cancer and Immunology Research, State Key Laboratory of Respiratory Disease, Guangzhou, China.
*These authors contributed equally to this work.
Citation:
Zhao T, Zeng J, Xu Y, Su Z, Chong Y, Ling T, Xu H, Shi H, Zhu M, Mo Q, Huang X, Li Y, Zhang X, Ni H, You Q. Chitinase-3 like-protein-1 promotes glioma progression via the NF-κB signaling pathway and tumor microenvironment reprogramming. Theranostics 2022; 12(16):6989-7008. doi:10.7150/thno.75069. https://www.thno.org/v12p6989.htm
Other stylesAbstract
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 CHI3L1low to CHI3L1high 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.
Keywords: CHI3L1, glioma, NF-κB, ACTN4, tumor microenvironment
Citation styles
APA
Zhao, T., Zeng, J., Xu, Y., Su, Z., Chong, Y., Ling, T., Xu, H., Shi, H., Zhu, M., Mo, Q., Huang, X., Li, Y., Zhang, X., Ni, H., You, Q. (2022). Chitinase-3 like-protein-1 promotes glioma progression via the NF-κB signaling pathway and tumor microenvironment reprogramming. Theranostics, 12(16), 6989-7008. https://doi.org/10.7150/thno.75069.
ACS
Zhao, T.; Zeng, J.; Xu, Y.; Su, Z.; Chong, Y.; Ling, T.; Xu, H.; Shi, H.; Zhu, M.; Mo, Q.; Huang, X.; Li, Y.; Zhang, X.; Ni, H.; You, Q. Chitinase-3 like-protein-1 promotes glioma progression via the NF-κB signaling pathway and tumor microenvironment reprogramming. Theranostics 2022, 12 (16), 6989-7008. DOI: 10.7150/thno.75069.
NLM
Zhao T, Zeng J, Xu Y, Su Z, Chong Y, Ling T, Xu H, Shi H, Zhu M, Mo Q, Huang X, Li Y, Zhang X, Ni H, You Q. Chitinase-3 like-protein-1 promotes glioma progression via the NF-κB signaling pathway and tumor microenvironment reprogramming. Theranostics 2022; 12(16):6989-7008. doi:10.7150/thno.75069. https://www.thno.org/v12p6989.htm
CSE
Zhao T, Zeng J, Xu Y, Su Z, Chong Y, Ling T, Xu H, Shi H, Zhu M, Mo Q, Huang X, Li Y, Zhang X, Ni H, You Q. 2022. Chitinase-3 like-protein-1 promotes glioma progression via the NF-κB signaling pathway and tumor microenvironment reprogramming. Theranostics. 12(16):6989-7008.
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