真核起始因子5A2（eIF5A2）在多种癌症中过度表达，而精氨酸介导的eIF5A去乙酰化（eIF5Ahpu）在eIF5A的大部分生物学功能中似乎是必不可少的，包括它在调节癌细胞增殖、上皮间质转化（EMT）和癌症干细胞（CSC）特性以及免疫细胞功能中的重要作用。在这里，我们研究了eIF5Ahpu在口腔鳞状细胞癌细胞（OSCCs）的生长以及OSCC诱导的M2型肿瘤相关巨噬细胞（TAMs）极化中的作用。TCGA数据集分析显示，在HNSCC中，eIF5A2的mRNA表达以及多胺（PA）代谢中的一些关键酶明显上调，这一结果得到了Western blot和IHC研究的证实。通过GC-7阻断eIF5Ahpu，但不是PA代谢的上游关键酶活性，显著抑制了OSCC细胞的增殖以及EMT和CSC相关基因的表达。此外，阻断eIF5Ahpu在体外强烈抑制了OSCC诱导的M2型TAM极化。更重要的是，在同种同源的正交的小鼠舌癌模型中，阻断eIF5Ahpu显著减缓了肿瘤的生长和M2型TAM的浸润/极化。因此，eIF5Ahpu在调节OSCC肿瘤细胞生长和M2型TAM极化方面发挥了双重功能。© 2023。作者。

Eukaryotic initiation factor 5A2 (eIF5A2) is overexpressed in many types of cancer, and spermidine-mediated eIF5A hypusination (eIF5Ahpu) appears to be essential to most of eIF5A's biological functions, including its important role in regulating cancer cell proliferation, epithelial-mesenchymal transition (EMT), and cancer stem cell (CSC) properties as well as immune cell functions. Here we investigated the role of eIF5Ahpu in the growth of oral squamous cell carcinoma cells (OSCCs) and OSCC-induced polarization of M2-like tumor-associated macrophages (TAMs). TCGA dataset analysis revealed an overall upregulation in the mRNA expression of eIF5A2 and several key enzymes involved in polyamine (PA) metabolism in HNSCC, which was confirmed by Western blot and IHC studies. Blocking eIF5Ahpu by GC-7 but not the upstream key enzyme activities of PA metabolism, remarkably inhibited cell proliferation and the expression of EMT- and CSC-related genes in OSCC cells. In addition, blocking eIF5Ahpu robustly inhibited OSCC-induced M2-like TAM polarization in vitro. More Importantly, blocking eIF5Ahpu dramatically retarded tumor growth and infiltration/polarization of M2-like TAM in a syngeneic orthotopic murine tongue SCC model. Thus, eIF5Ahpu plays dual functions in regulating tumor cell growth and polarization of M2-TAMs in OSCC.© 2023. The Author(s).