The epithelial–mesenchymal transition (EMT) is a pivotal step involved in cancer recurrence and metastasis. In addition, the activation of the EMT program can induce a cancer stem cell (CSC)-like phenotype and programmed death-ligand 1 (PD-L1) expression in head and neck squamous cell carcinoma (HNSCC). The CMTM family has reported as an important regulator in this process. Here, we investigated the role of CMTM4 in HNSCC. We indicated that CMTM4 was overexpressed in human and mouse HNSCC samples and in HNSCC cell lines by immunohistochemistry and Western blot. A high expression level of CMTM4 was correlated with advanced lymph node metastasis and a negative prognosis. CMTM4-knockdown by small interfering RNA downregulated the EMT process and inhibited the migration and invasion abilities of tumor cells. Moreover, knockdown of CMTM4 decreased CSC-associated markers via the protein kinase B pathway. Notably, CMTM4-knockdown inhibited the expression of interferon-γ induced PD-L1 in HNSCC cells. A positive correlation was found between CMTM4 expression and CD8⁺ and PD-1⁺ cell density in the stroma. Our findings indicated that CMTM4 may play an important role in regulating EMT/CSC phenotypes and PD-L1 expression. This study may reinforce the interest in CMTM4 as a potential target for the prognosis and treatment of HNSCC.

中文翻译：

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CMTM4 调节头颈部鳞状细胞癌的上皮间质转化和 PD-L1 表达

上皮间质转化（EMT）是癌症复发和转移的关键步骤。此外，EMT 程序的激活可以在头颈部鳞状细胞癌 (HNSCC) 中诱导癌症干细胞 (CSC) 样表型和程序性死亡配体 1 (PD-L1) 表达。据报道，CMTM 系列是该过程中的重要调节器。在这里，我们研究了 CMTM4 在 HNSCC 中的作用。我们通过免疫组织化学和蛋白质印迹表明 CMTM4 在人和小鼠 HNSCC 样品和 HNSCC 细胞系中过表达。CMTM4 的高表达水平与晚期淋巴结转移和阴性预后相关。CMTM4-knockdown 通过小干扰 RNA 下调 EMT 过程并抑制肿瘤细胞的迁移和侵袭能力。而且，CMTM4 的敲低通过蛋白激酶 B 途径减少了 CSC 相关标志物。值得注意的是，CMTM4 敲低抑制了干扰素-γ 诱导的 PD-L1 在 HNSCC 细胞中的表达。CMTM4 表达与 CD8 呈正相关⁺和 PD-1 ⁺基质中的细胞密度。我们的研究结果表明，CMTM4 可能在调节 EMT/CSC 表型和 PD-L1 表达方面发挥重要作用。这项研究可能会加强对 CMTM4 作为 HNSCC 预后和治疗潜在靶点的兴趣。