不断积累的证据表明，细胞因子在肿瘤来源的细胞外囊泡 (EVs) 中丰富，并在各种类型的癌症中广泛参与肿瘤发生，包括结直肠癌 (CRC)。然而，来自结直肠癌细胞分泌的 EVs 中细胞因子的功能仍然大多未知。本研究发现，在 CRC 患者血清样本和 CRC 细胞系中，TNF-α 在 EVs 中被提高，其表达与结直肠癌的侵袭性特征相关。EV TNF-α 的分泌取决于突触体结合蛋白 23 (SNAP23)。功能实验揭示，EV TNF-α 通过作用于 SNAP23 促进了 CRC 细胞的转移，通过靶向 SNAP23 促进了 NF-κB 途径的激活。在机制上，EV TNF-α /NF-κB 轴通过转录上调 SNAP23，增强了纤维连接蛋白亚基 beta-3 (LAMB3) 的表达，从而激活了 PI3K/AKT 信号通路，促进了 CRC 的进展。根据我们的发现，可以得出结论，EV TNF-α 通过 SNAP23 在 CRC 进展中发挥了致癌作用，反过来促进了 EV TNF-α 的分泌，因此，EV TNF-α /SNAP23 轴可能作为 CRC 的诊断生物标志物和潜在治疗靶点。版权所有 © 2023 Elsevier Inc.

Accumulating evidence have demonstrated that cytokines are enriched in tumor-derived extracellular vesicles (EVs) and widely involved in tumorigenesis of various types of carcinomas, including colorectal cancer (CRC). Nevertheless, the functions of cytokines in EVs secreted from colorectal cancer cells remain largely unknown. In the present study, we found that TNF-α was elevated in EVs from CRC patient serum samples and CRC cell lines, of which the expression was associated with aggressive features of colorectal cancer. EV TNF-α secretion is dependent on synaptosome-associated protein 23 (SNAP23). Functional experiments revealed that EV TNF-α promotes CRC cell metastasis via the NF-κB pathway by targeting SNAP23. Mechanistically, SNAP23 was transcriptionally upregulated by EV TNF-α/NF-κB axis to enhance the expression of laminin subunit beta-3 (LAMB3), thereby activating the PI3K/AKT signaling pathway and consequently facilitate CRC progression. Based on our findings, we could conclude that EV TNF-α plays an oncogenic role in CRC progression through SNAP23, which in turn promotes EV TNF-α secretion, suggesting that EV TNF-α/SNAP23 axis may serve as a diagnostic biomarker and potential therapeutic target for CRC.Copyright © 2023. Published by Elsevier Inc.