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Extracellular vesicles-transferred SBSN drives glioma aggressiveness by activating NF-κB via ANXA1-dependent ubiquitination of NEMO

Abstract

Glioma is the most common malignant primary brain tumor with aggressiveness and poor prognosis. Although extracellular vesicles (EVs)-based cell-to-cell communication mediates glioma progression, the key molecular mediators of this process are still not fully understood. Herein, we elucidated an EVs-mediated transfer of suprabasin (SBSN), leading to the aggressiveness and progression of glioma. High levels of SBSN were positively correlated with clinical grade, predicting poor clinical prognosis of patients. Upregulation of SBSN promoted, while silencing of SBSN suppressed tumorigenesis and aggressiveness of glioma cells in vivo. EVs-mediated transfer of SBSN resulted in an increase in SBSN levels, which promoted the aggressiveness of glioma cells by enhancing migration, invasion, and angiogenesis of recipient glioma cells. Mechanistically, SBSN activated NF-κB signaling by interacting with annexin A1, which further induced Lys63-linked and Met1-linear polyubiquitination of NF-κB essential modulator (NEMO). In conclusion, the communication of SBSN-containing EVs within glioma cells drives the formation and development of tumors by activating NF-κB pathway, which may provide potential therapeutic target for clinical intervention in glioma.

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Fig. 1: SBSN is upregulated in glioma and associates with glioma progression.
Fig. 2: SBSN enhances glioma aggressiveness in vivo.
Fig. 3: SBSN enhances glioma aggressiveness in vitro.
Fig. 4: EVs-transferred SBSN promotes glioma aggressiveness.
Fig. 5: EVs-transferred SBSN activates NF-κB signaling pathway.
Fig. 6: EVs-transferred SBSN activates NF-κB through ANXA1.
Fig. 7: EVs-transferred SBSN activates NF-κB through ANXA1-dependent NEMO ubiquitination.

Data availability

For survival analysis of glioma patients, the Chinese Glioma Genome Atlas (CGGA) and the Cancer Genome Atlas (TCGA) datasets were used. All other data supporting the findings of this study are available within the article and its Supplementary information files and on reasonable request from the corresponding author.

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Funding

This work was supported by the Basic and Applied Research Projects of Guangzhou Science and Technology Bureau (202002030067), the Natural Science Foundation of China (82273464, 81972619, 81672874, and 81972399), the Natural Science Foundation of Guangdong Province (2021A1515012477 and 2022A1515012260), the Key Discipline of Guangzhou Education Bureau (Basic Medicine) (201851839), the Natural Science Foundation research team of Guangdong Province (2018B030312001), the open research funds from the Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital (202011-202), the Innovative Academic Team of Guangzhou Education System (1201610014), and the Guangzhou key medical discipline construction project fun.

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LJ and JL developed the original idea, designed the study, analyzed data, and wrote the manuscript. HC, XC, ZZ and WB contributed to the development of the protocol and performed most of the experiments and data analysis. ZG, DL, XX, PZ, CY and ZZ contributed to the in vitro biological experiments and data analysis. HC, ZZ, ZG and XX performed the in vivo experiments and data analysis. ZZ, JP, XK, DZ, JY and LW contributed to clinical data collection and statistical analysis. RT, ZF, LZ and HH provided the bioinformatics analysis. DT assisted in data interpretation and edited the manuscript.

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Correspondence to Jinbao Liu or Lili Jiang.

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Chen, H., Chen, X., Zhang, Z. et al. Extracellular vesicles-transferred SBSN drives glioma aggressiveness by activating NF-κB via ANXA1-dependent ubiquitination of NEMO. Oncogene 41, 5253–5265 (2022). https://doi.org/10.1038/s41388-022-02520-6

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