E26转化特异性（ETS）因子已被确认为人类肿瘤发生的关键调节因子。在此，我们旨在研究ETS变异转录因子5（ETV5）在头颈鳞状细胞癌（HNSCC）中的表达模式、生物学作用和临床意义。通过生物信息学分析和原位免疫组化染色在原发样本中确定了HNSCC中ETV5的表达模式。评估了其丰度与临床病理参数以及患者生存率之间的关联。利用无菌和体内模型，结合培养物形成、CCK-8、流式细胞术、创伤愈合、及Transwell侵袭实验，确定了ETV5沉默后细胞外和内的表型变化。通过ChIP-qPCR确定了ETV5在Slug启动子上的潜在结合。ETV5在HNSCC样本中明显过表达。其过表达与侵袭性特征和生存率降低显著相关。ETV5沉默显著抑制了细胞外和内的增殖、迁移、侵袭，并诱导了凋亡，并在体内削弱了肿瘤生长。此外，ETV5通过结合HNSCC细胞中Slug启动子区域，激活了Slug转录。ETV5高Slughigh患者在多个HNSCC队列中的生存率最差。我们的发现揭示了ETV5作为HNSCC进展的新的预后生物标志物和潜在的致癌基因，可能通过激活Slug转录。 © 2023 Wiley Periodicals LLC.

E26 transformation-specific (ETS) factors have emerged as key mediators underlying human tumorigenesis. Here, we sought to characterize the expression pattern, biological roles, and clinical significance of ETS Variant Transcription Factor 5 (ETV5) in head neck squamous cell carcinoma (HNSCC).ETV5 expression pattern in HNSCC was determined by bioinformatics interrogations and immunohistochemical staining in primary samples. The associations between its abundance with clinicopathological parameters, and patient survival were evaluated. Colony formation, CCK-8, flow cytometry, wound healing, and Transwell invasion assays, as well as xenograft models, were utilized to determine the phenotypic changes after ETV5 silencing in vitro and vivo. The potential binding of ETV5 in the Slug promoter was determined by ChIP-qPCR.ETV5 was significantly overexpressed in HNSCC samples. Its overexpression is significantly associated with aggressiveness features and reduced survival. ETV5 knockdown significantly inhibited cell proliferation, migration, invasion, and induced apoptosis in vitro, and impaired tumor growth in vivo. Moreover, ETV5-activated Slug transcription by binding its promoter region in HNSCC cells. Patients with ETV5high Slughigh had the worst survival across multiple HNSCC cohorts.Our findings reveal that ETV5 serves as a novel prognostic biomarker and putative oncogene for HNSCC progression likely by activating Slug transcription.© 2023 Wiley Periodicals LLC.