细胞外囊泡（EV）在触发肿瘤侵袭行为中发挥着至关重要的作用。然而，肿瘤细胞产生 EV 的能量过程仍然知之甚少。在这里，我们证明了 β-己糖胺酶 B (HEXB) 参与介导氧化应激反应中的 EV 释放，从而促进肝细胞癌 (HCC) 的发展。从机制上讲，活性氧 (ROS) 刺激转录因子 EB (TFEB) 的核转位，导致 HEXB 及其反义 lncRNA HEXB-AS 上调。 HEXB-AS可以与HEXB结合形成蛋白质/RNA复合物，从而提高HEXB的蛋白质稳定性。稳定的 HEXB 与溶酶体相关膜糖蛋白 1 (LAMP1) 相互作用，破坏溶酶体-多泡体 (MVB) 融合，从而保护 EV 免遭降解。 HEXB 的敲低可有效抑制 EV 释放，并在体外和体内抑制 HCC 生长。此外，M-31850 靶向 HEXB 可显着抑制 HCC 生长，特别是与外泌体释放抑制剂 GW4869 联合使用时。我们的结果强调了 HEXB 作为调节剂在 HCC 发展过程中促进 EV 释放的关键作用。© 2024 作者。 《Journal of Extracellular Vesicles》由 Wiley periodicals LLC 代表国际细胞外囊泡学会出版。

Extracellular vesicles (EVs) play a crucial role in triggering tumour-aggressive behaviours. However, the energetic process by which tumour cells produce EVs remains poorly understood. Here, we demonstrate the involvement of β-hexosaminidase B (HEXB) in mediating EV release in response to oxidative stress, thereby promoting the development of hepatocellular carcinoma (HCC). Mechanistically, reactive oxygen species (ROS) stimulate the nuclear translocation of transcription factor EB (TFEB), leading to the upregulation of both HEXB and its antisense lncRNA HEXB-AS. HEXB-AS can bind HEXB to form a protein/RNA complex, which elevates the protein stability of HEXB. The stabilized HEXB interacts with lysosome-associated membrane glycoprotein 1 (LAMP1), disrupting lysosome-multivesicular body (MVB) fusion, which protects EVs from degradation. Knockdown of HEXB efficiently inhibits EV release and curbs HCC growth both in vitro and in vivo. Moreover, targeting HEXB by M-31850 significantly inhibits HCC growth, especially when combined with GW4869, an inhibitor of exosome release. Our results underscore the critical role of HEXB as a modulator that promotes EV release during HCC development.© 2024 The Author(s). Journal of Extracellular Vesicles published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.