与细胞周期进程有关的基因可以被认为是人类癌症的关键因素。然而，在非小细胞肺癌（NSCLC）中参与细胞周期调节的基因尚未报告。因此，有必要评估所有类型癌症中与细胞周期有关的基因，特别是NSCLC。本研究构成了第一个细胞周期信号通路的泛癌症景观。基于细胞周期信号的聚类分析用于确定NSCLC的潜在分子异质性。进一步，研究了三个聚类之间的肿瘤免疫微环境、代谢重建和细胞死亡差异。进行免疫组化验证ZWINT基因的蛋白水平并检查其与临床特征的关系。还进行了ZWINT基因的生物信息学分析和实验验证。首先，泛癌症分析提供了细胞周期信号的概览并强调了其在癌症中的关键作用。大部分细胞周期调节因子在肺腺癌（LUAD）中起风险作用；然而，某些细胞周期基因在肺鳞状细胞癌（LUSC）中起保护作用。聚类分析揭示了NSCLC患者的三种潜在亚型。具有高细胞周期活动的LUAD患者与更差的预后相关；而具有高细胞周期活性的LUSC患者则与更长的生存时间相关。此外，上述三种NSCLC亚型表现出明显不同的免疫微环境、代谢重建和细胞死亡途径。ZWINT是细胞信号通路的成员，与LUAD患者的预后显著相关。一系列实验验证了与癌组织相比，NSCLC中ZWINT的表达水平更高。ZWINT诱导的上皮间质转化（EMT）的激活可能是肿瘤进展的原因。本研究揭示了细胞周期基因在NSCLC中的调节功能，并且基于细胞周期相关基因的分子分类可以评估NSCLC患者的不同预后。发现ZWINT表达在NSCLC组织中显著上调，可能通过激活EMT通路促进肿瘤进展。版权所有©2023 Cao、Xiao、Zhang和Li。

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.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.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.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 via activation of the EMT pathway.Copyright © 2023 Cao, Xiao, Zhang and Li.