PDF(Pubmed)
Abstract：
Extracellular vesicles (EVs) have recently received increasing attention as essential mediators of communication between tumor cells and their microenvironments. Tumor-associated macrophages (TAMs) play a proangiogenic role in various tumors, especially head and neck squamous cell carcinoma (HNSCC), and angiogenesis is closely related to tumor growth and metastasis. This research focused on exploring the mechanisms by which EVs derived from TAMs modulate tumor angiogenesis in HNSCC. Our results indicated that TAMs infiltration correlated positively with microvascular density in HNSCC. Then we collected and identified EVs from TAMs. In the microfluidic chip, TAMs derived EVs significantly enhanced the angiogenic potential of pHUVECs and successfully induced the formation of perfusable blood vessels. qPCR and immunofluorescence analyses revealed that EVs from TAMs transferred miR-21-5p to endothelial cells (ECs). And targeting miR-21-5p of TAMs could effectively inhibit TAM-EVs induced angiogenesis. Western blot and tube formation assays showed that miR-21-5p from TAM-EVs downregulated LATS1 and VHL levels but upregulated YAP1 and HIF-1α levels, and the inhibitors of YAP1 and HIF-1α could both reduce the miR-21-5p enhanced angiogenesis in HUVECs. The in vivo experiments further proved that miR-21-5p carried by TAM-EVs promoted the process of tumor angiogenesis via YAP1/HIF-1α axis in HNSCC. Conclusively, TAM-derived EVs transferred miR-21-5p to ECs to target the mRNA of LATS1 and VHL, which inhibited YAP1 phosphorylation and subsequently enhanced YAP1-mediated HIF-1α transcription and reduced VHL-mediated HIF-1α ubiquitination, contributing to angiogenesis in HNSCC. These findings present a novel regulatory mechanism of tumor angiogenesis, and miR-21-5p/YAP1/HIF-1α might be a potential therapeutic target for HNSCC.
摘要：
细胞外囊泡（EV）最近作为肿瘤细胞与其微环境之间通讯的重要介质受到越来越多的关注。肿瘤相关巨噬细胞（TAMs）在各种肿瘤中发挥促血管生成作用，尤其是头颈部鳞状细胞癌（HNSCC），血管生成与肿瘤的生长和转移密切相关。这项研究的重点是探索源自TAM的EV调节HNSCC中肿瘤血管生成的机制。我们的结果表明，在HNSCC中，TAMs浸润与微血管密度呈正相关。然后我们从TAM中收集并识别了EV。在微流控芯片中，TAM衍生的EV显着增强了pHUVEC的血管生成潜力，并成功诱导了可灌注血管的形成。qPCR和免疫荧光分析显示，来自TAM的EV将miR-21-5p转移到内皮细胞（EC）。而靶向miR-21-5p的TAM能有效抑制TAM-EV诱导的血管生成。Westernblot和试管形成实验显示，来自TAM-EV的miR-21-5p下调LATS1和VHL水平，但上调YAP1和HIF-1α水平，YAP1和HIF-1α的抑制剂均可降低miR-21-5p增强HUVECs的血管生成。体内实验进一步证明，TAM-EV携带的miR-21-5p通过YAP1/HIF-1α轴促进HNSCC肿瘤血管生成过程。最后，TAM衍生的EV将miR-21-5p转移到EC中以靶向LATS1和VHL的mRNA，抑制YAP1磷酸化，随后增强YAP1介导的HIF-1α转录和减少VHL介导的HIF-1α泛素化，有助于HNSCC中的血管生成。这些发现提出了一种新的肿瘤血管生成调控机制,miR-21-5p/YAP1/HIF-1α可能是HNSCC的潜在治疗靶点。
