鉴定非小细胞肺癌的细胞周期特征及其与肿瘤免疫微环境、细胞死亡途径和代谢重编程的关系。

BACKGROUND: The genes related to the cell cycle progression could be considered the key factors in human cancers. However, the genes involved in cell cycle regulation in non-small cell lung cancer (NSCLC) have not yet been reported. Therefore, it is necessary to evaluate the genes related to the cell cycle in all types of cancers, especially NSCLC. METHODS: This study constituted the first pan-cancer landscape of cell cycle signaling. Cluster analysis based on cell cycle signaling was conducted to identify the potential molecular heterogeneity of NSCLC. Further, the discrepancies in the tumor immune microenvironment, metabolic remodeling, and cell death among the three clusters were investigated. Immunohistochemistry was performed to validate the protein levels of the ZWINT gene and examine its relationship with the clinical characteristics. Bioinformatics analyses and experimental validation of the ZWINT gene were also conducted. RESULTS: First, pan-cancer analysis provided an overview of cell cycle signaling and highlighted its crucial role in cancer. A majority of cell cycle regulators play risk roles in lung adenocarcinoma (LUAD); however, some cell cycle genes play protective roles in lung squamous cell carcinoma (LUSC). Cluster analysis revealed three potential subtypes for patients with NSCLC. LUAD patients with high cell cycle activities were associated with worse prognosis; while, LUSC patients with high cell cycle activities were associated with a longer survival time. Moreover, the above three subtypes of NSCLC exhibited distinct immune microenvironments, metabolic remodeling, and cell death pathways. ZWINT, a member of the cell signaling pathway, was observed to be significantly associated with the prognosis of LUAD patients. A series of experiments verified the higher expression levels of ZWINT in NSCLC compared to those in paracancerous tissues. The activation of epithelial-mesenchymal transition (EMT) induced by ZWINT might be responsible for tumor progression. CONCLUSION: This study revealed the regulatory function of the cell cycle genes in NSCLC, and the molecular classification based on cell cycle-associated genes could evaluate the different prognoses of patients with NSCLC. ZWINT expression was found to be significantly upregulated in NSCLC tissues, which might promote tumor progression activation of the EMT pathway.

背景：与细胞周期进展相关的基因可以被认为是人类癌症的关键因素。然而，非小细胞肺癌（NSCLC）中涉及细胞周期调控的基因尚未报道。因此，有必要评估所有类型癌症中与细胞周期相关的基因，尤其是 NSCLC。

方法：本研究构成了细胞周期信号的泛癌症景观的首次研究。基于细胞周期信号的聚类分析用于鉴定 NSCLC 的潜在分子异质性。此外，还研究了三个聚类之间肿瘤免疫微环境、代谢重塑和细胞死亡的差异。进行免疫组织化学染色以验证 ZWINT 基因的蛋白水平，并检查其与临床特征的关系。还对 ZWINT 基因进行了生物信息学分析和实验验证。

结果：首先，泛癌症分析提供了细胞周期信号的概述，并强调了其在癌症中的关键作用。大多数细胞周期调节剂在肺腺癌（LUAD）中发挥风险作用；然而，一些细胞周期基因在肺鳞状细胞癌（LUSC）中发挥保护作用。聚类分析显示 NSCLC 患者有三个潜在亚型。具有高细胞周期活性的 LUAD 患者预后较差；而具有高细胞周期活性的 LUSC 患者生存时间较长。此外，这三种 NSCLC 亚型表现出不同的免疫微环境、代谢重塑和细胞死亡途径。ZWINT，细胞信号通路的一个成员，与 LUAD 患者的预后显著相关。一系列实验验证了 ZWINT 在 NSCLC 中的表达水平明显高于癌旁组织。ZWINT 诱导的上皮-间充质转化（EMT）的激活可能是肿瘤进展的原因。

结论：本研究揭示了细胞周期基因在 NSCLC 中的调节功能，基于与细胞周期相关基因的分子分类可以评估 NSCLC 患者不同的预后。发现 ZWINT 在 NSCLC 组织中的表达明显上调，可能通过激活 EMT 通路促进肿瘤进展。