Department of Oral Pathology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR, China.
Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, PR, China.
J Extracell Vesicles. 2023 Feb;12(2):e12310. doi: 10.1002/jev2.12310.
Tumour cells under hypoxia tend to modulate the number and contents of extracellular vesicles (EVs) to regulate the tumour microenvironment (TME) and thus promote tumour progression. However, the mechanism of how hypoxia influences the secretion of EVs remains to be elucidated. Here, we confirm the increased production of EVs in head and neck squamous cell carcinoma (HNSCC) cells under hypoxia, where endosome-derived EVs are the main subtype affected by insufficient O . The accumulation of hypoxia-inducible factor-1α (HIF-1α) under hypoxia directly downregulates the expression of ATP6V1A, which is pivotal to maintain the homeostasis of lysosomes. Subsequently, impaired lysosomal degradation contributes to the reduced fusion of multivesicular bodies (MVBs) with lysosomes and enables the secretion of intraluminal vesicles (ILVs) as EVs. These findings establish a HIF-1α-regulated lysosomal dysfunction-EV release axis and provide an exquisite framework to better understand EV biogenesis.
在缺氧下，肿瘤细胞往往会调节细胞外囊泡（EVs）的数量和内容，以调节肿瘤微环境（TME），从而促进肿瘤进展。然而，缺氧影响 EVs 分泌的机制仍有待阐明。在这里，我们证实了缺氧下头颈部鳞状细胞癌（HNSCC）细胞中 EVs 的产生增加，其中内体衍生的 EVs 是受 O 不足影响的主要亚型。缺氧诱导因子-1α（HIF-1α）在缺氧下的积累直接下调 ATP6V1A 的表达，这对维持溶酶体的内环境稳定至关重要。随后，溶酶体降解受损导致多泡体（MVB）与溶酶体融合减少，并使腔内囊泡（ILVs）作为 EVs 分泌。这些发现建立了一个由 HIF-1α 调节的溶酶体功能障碍-EV 释放轴，并为更好地理解 EV 的生物发生提供了一个精细的框架。
