Exosomal miR-4745-5p/3911 from N2-polarized tumor-associated neutrophils promotes gastric cancer metastasis by regulating SLIT2

被引:6
|
作者
Zhang, Jiahui [1 ,3 ]
Yu, Dan [1 ]
Ji, Cheng [1 ]
Wang, Maoye [1 ]
Fu, Min [1 ]
Qian, Yu [1 ]
Zhang, Xiaoxin [1 ]
Ji, Runbi [1 ]
Li, Chong [3 ]
Gu, Jianmei [2 ]
Zhang, Xu [1 ]
机构
[1] Jiangsu Univ, Sch Med, Dept Lab Med, Zhenjiang 212013, Jiangsu, Peoples R China
[2] Nantong Univ, Nantong Tumor Hosp, Affiliated Tumor Hosp, Dept Clin Lab Med, Nantong 226300, Jiangsu, Peoples R China
[3] Jiangsu Univ, Affiliated Kunshan Hosp, Kunshan Biomed Big Data Innovat Applicat Lab, Dept Clin Lab, ,Kunshan, Kunshan 215300, Jiangsu, Peoples R China
基金
中国国家自然科学基金;
关键词
Exosomes; Gastric cancer; Tumor-associated neutrophils; N2; polarization; Metastasis; SLIT2; EXTRACELLULAR VESICLES;
D O I
10.1186/s12943-024-02116-6
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Tumor cells remodel the phenotype and function of tumor microenvironment (TME) cells to favor tumor progression. Previous studies have shown that neutrophils in TME are polarized to N2 tumor-associated neutrophils (TANs) by tumor derived factors, thus promoting tumor growth and metastasis, angiogenesis, therapy resistance, and immunosuppression. Exosomes act as critical intercellular messengers in human health and diseases including cancer. So far, the biological roles of exosomes from N2 TANs in gastric cancer have not been well characterized. Herein, we represented the first report that exosomes from N2 TANs promoted gastric cancer metastasis in vitro and in vivo. We found that exosomes from N2 TANs transferred miR-4745-5p/3911 to gastric cancer cells to downregulate SLIT2 (slit guidance ligand 2) gene expression. Adenovirus-mediated overexpression of SLIT2 reversed the promotion of gastric cancer metastasis by N2 TANs derived exosomes. We further revealed that gastric cancer cells induced glucose metabolic reprogramming in neutrophils through exosomal HMGB1 (high mobility group protein B1)/NF-kappa B pathway, which mediated neutrophil N2 polarization and miR-4745-5p/3911 upregulation. We further employed ddPCR (droplet digital PCR) to detect the expression of miR-4745-5p/3911 in N2 TANs exosomes from human serum samples and found their increased levels in gastric cancer patients compared to healthy controls and benign gastric disease patients. Conclusively, our results indicate that N2 TANs facilitate cancer metastasis via regulation of SLIT2 in gastric cancer cells by exosomal miR-4745-5p/3911, which provides a new insight into the roles of TME cells derived exosomes in gastric cancer metastasis and offers a potential biomarker for gastric cancer diagnosis.
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页数:17
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