STC1与喉鳞状细胞癌的肿瘤进展和抑制性生态位相关。

文献信息

中文摘要

背景： 喉鳞状细胞癌（LSCC）表现出高复发率和治疗耐药性。我们旨在研究斯钙素-1（STC1）在LSCC发病机制中尚未明确的角色。
方法： 从公共数据库获取LSCC患者的单细胞RNA测序（RNA-seq）数据和临床信息。评估STC1的预后差异和诊断效率。通过Spearman方法研究基因相关性。使用clusterProfiler进行富集分析，并使用CIBERSORT评估免疫浸润。最后，我们使用单细胞RNA测序（scRNA-seq）分析STC1在细胞类型中的特异性表达分布，以及STC1+细胞与T细胞亚群之间配体-受体相互作用的细胞通讯。
结果： 上调的STC1与LSCC中的肿瘤转移和疾病分期相关。它与涉及细胞外基质（ECM）重塑、上皮-间质转化（EMT）、磷脂酰肌醇3-激酶（PI3K）-蛋白激酶B（Akt）和表皮生长因子受体（EGFR）-酪氨酸激酶抑制剂（TKI）耐药性的基因相关。高STC1表达与免疫抑制微环境相关，M0巨噬细胞增加和CD8+ T细胞减少，并与免疫检查点[程序性死亡配体1（PD-L1）、细胞毒性T淋巴细胞相关蛋白4（CTLA4）、T细胞免疫球蛋白和ITIM结构域（TIGIT）、T细胞免疫球蛋白和含粘蛋白结构域蛋白3（TIM-3）]正相关。单细胞分析将STC1定位在上皮细胞中，STC1+上皮细胞在癌变过程中显示内质网（ER）应激、炎症信号和EMT富集。细胞-细胞通讯分析显示，与STC1-上皮细胞相比，STC1+上皮细胞通过转化生长因子-β（TGF-β）和B-和T-淋巴细胞衰减器（BTLA）通路中更多的配体-受体对与T细胞亚群相互作用。
结论： 这些发现表明STC1与LSCC中的免疫逃逸和恶性进展特征强烈相关，提示靶向STC1可能重编程免疫抑制微环境并改善治疗结果。

英文摘要

BACKGROUND: Laryngeal squamous cell carcinoma (LSCC) exhibits high recurrence and therapy resistance. We aimed to investigate the undefined role of Stanniocalcin-1 (STC1) in LSCC pathogenesis.
METHODS: The single-cell RNA sequencing (RNA-seq) data and the clinical information of LSCC patients were acquired from the public database. Prognostic differences and diagnostic efficiency of STC1 were assessed. The gene correlation was investigated by Spearman method. Enrichment analysis was performed using clusterProfiler, and immune infiltration was assessed with CIBERSORT. Finally, we analyzed the distribution of specific STC1 expression in cell types using single-cell RNA sequencing (scRNA-seq) analysis, and cell communication for ligand-receptor interactions between STC1+ cells and T cell subsets.
RESULTS: The upregulated STC1 was linked to tumor metastasis and disease stage in LSCC. It correlated with genes involved in extracellular matrix (ECM) remodeling, epithelial-mesenchymal transition (EMT), phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt), and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) resistance. High STC1 expression was linked to an immunosuppressive microenvironment, with increased M0 macrophages and reduced CD8+ T cells, and was positively correlated with the immune checkpoints [programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), T cell immunoglobulin and ITIM domain (TIGIT), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3)]. Single-cell analysis localized STC1 to epithelial cells, with STC1+ epithelial cells showing enriched endoplasmic reticulum (ER) stress, inflammatory signaling, and EMT during carcinogenesis. Cell-cell communication analysis revealed that STC1+ epithelial cells engage T cell subsets through more ligand-receptor pairs in the transforming growth factor-beta (TGF-β) and B- and T-lymphocyte attenuator (BTLA) pathways compared to STC1- epithelial cells.
CONCLUSIONS: These findings indicate STC1 is strongly correlated with signatures of immune evasion and malignant progression in LSCC, suggesting that targeting STC1 may reprogram the immunosuppressive microenvironment and improve therapeutic outcomes.