Hu Yan, Qiu Yongle, Wang Wenjing, He Xin, Wu Qian, Cai Tianyi, Lu Shuojing, Zhuang Zhizheng
Department of Stomatology, Affiliated Hospital of Hebei University, Baoding, 071000, Hebei, PR China.
Department of Stomatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050017, Hebei, PR China.
Exp Cell Res. 2025 Jul 15;450(2):114661. doi: 10.1016/j.yexcr.2025.114661. Epub 2025 Jun 27.
Cancer stemness plays a pivotal role in driving metastasis and recurrence in oral squamous cell carcinoma (OSCC). Although immune-tumor cell interactions regulate cancer stemness plasticity, the underlying mechanisms remain incompletely characterized. This study aimed to explore the key signaling axis mediating tumor-immune cell crosstalk that governs cancer stemness in OSCC. Single-cell RNA sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) database revealed eight major cell clusters and five epithelial sub-clusters within OSCC. CytoTRACE analysis revealed that epithelial sub-cluster 1 exhibiting the highest stemness potential, from which ten stemness-related genes were derived. Among these, LY6E was screened as an enhancer-controlled gene in OSCC cells. LY6E knockdown significantly suppressed self-renewal and proliferation of OSCC cells in vitro, as well as tumor growth in vivo. Mechanistically, NF-κB bound to the enhancer of LY6E to drive its transcription. Cell-cell communication analysis highlighted that macrophages are the dominant immune cells interacting with malignant cells. Macrophage-derived TNFα facilitated NF-κB enrichment at the LY6E enhancer regions and upregulated its transcription in OSCC cells. TNFα stimulation, exposure to macrophage-conditioned medium, or coculture with macrophages significantly promoted the self-renewal and proliferation of OSCC cells, but these effects were abolished by LY6E knockdown or NF-κB inhibition. In conclusion, the NF-κB/LY6E axis is a key signaling hub in response to macrophage-OSCC cell interaction in promoting cancer stemness.
癌症干性在口腔鳞状细胞癌（OSCC）的转移和复发中起关键作用。尽管免疫肿瘤细胞相互作用调节癌症干性可塑性，但其潜在机制仍未完全阐明。本研究旨在探索介导肿瘤免疫细胞串扰的关键信号轴，该串扰控制OSCC中的癌症干性。来自基因表达综合数据库（GEO）的单细胞RNA测序（scRNA-seq）数据揭示了OSCC内的八个主要细胞簇和五个上皮亚簇。细胞追踪分析显示上皮亚簇1具有最高的干性潜能，从中衍生出十个与干性相关的基因。其中，LY6E被筛选为OSCC细胞中的增强子控制基因。LY6E敲低显著抑制了OSCC细胞在体外的自我更新和增殖，以及体内的肿瘤生长。机制上，NF-κB与LY6E的增强子结合以驱动其转录。细胞间通讯分析突出显示巨噬细胞是与恶性细胞相互作用的主要免疫细胞。巨噬细胞衍生的TNFα促进了NF-κB在LY6E增强子区域的富集，并上调了其在OSCC细胞中的转录。TNFα刺激、暴露于巨噬细胞条件培养基或与巨噬细胞共培养显著促进了OSCC细胞的自我更新和增殖，但这些作用被LY6E敲低或NF-κB抑制所消除。总之，NF-κB/LY6E轴是响应巨噬细胞-OSCC细胞相互作用促进癌症干性的关键信号枢纽。
