Wang Yiman, Xiao Bolin, Li Jinbang, Zhang Mengyao, Zhang Linzhou, Chen Liguo, Zhang Jing, Chen Gang, Zhang Wei
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China.
Department of Thyroid and Breast Surgery, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
Cell Signal. 2025 Mar;127:111546. doi: 10.1016/j.cellsig.2024.111546. Epub 2024 Dec 2.
Small extracellular vesicles (sEVs) act as crucial messengers that transmit biological signals in hypoxic tumor microenvironment (TME), significantly impacting cancer progression. However, the precise mechanism by which hypoxia influences sEV biogenesis remains poorly understood. In this study, we observed increased sEV secretion and alterations in cargo composition in head and neck squamous cell carcinoma (HNSCC) cells under hypoxic conditions. We found that hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), a key component of the endosomal sorting complexes required for transport (ESCRT), was upregulated during hypoxia. This upregulation activated the endosomal system and reduced degradation of multivesicular bodies (MVBs). HRS depletion altered the packaging of protein cargoes such as mitochondria-related proteins into sEVs under hypoxia, and these cargoes promoted a pro-tumorigenic phenotype of macrophages. Importantly, we demonstrated that HRS is transcriptionally activated by hypoxia inducible factor-1α (HIF-1α). Spatial transcriptomics and immunohistochemistry revealed a positive correlation between HRS and HIF-1α. These findings establish a link between the hypoxic response, sEV biogenesis, and cargo packaging, enhancing our understanding of how the hypoxic TME influences sEV biogenesis in HNSCC cells.
小细胞外囊泡（sEVs）作为关键信使，在缺氧肿瘤微环境（TME）中传递生物信号，对癌症进展有显著影响。然而，缺氧影响sEV生物发生的精确机制仍知之甚少。在本研究中，我们观察到缺氧条件下，头颈部鳞状细胞癌（HNSCC）细胞中sEV分泌增加且货物组成发生改变。我们发现，内体分选转运复合体（ESCRT）的关键成分、肝细胞生长因子调节的酪氨酸激酶底物（HRS）在缺氧期间上调。这种上调激活了内体系统并减少了多囊泡体（MVBs）的降解。HRS缺失改变了缺氧条件下线粒体相关蛋白等蛋白质货物向sEVs中的包装，并且这些货物促进了巨噬细胞的促肿瘤表型。重要的是，我们证明HRS由缺氧诱导因子-1α（HIF-1α）转录激活。空间转录组学和免疫组织化学显示HRS与HIF-1α之间呈正相关。这些发现建立了缺氧反应、sEV生物发生和货物包装之间的联系，增进了我们对缺氧TME如何影响HNSCC细胞中sEV生物发生的理解。
