Mu Qiuqiao, Zhang Han, Wang Kai, Tan Lin, Li Xin, Sun Daqiang
Clinical School of Thoracic, Tianjin Medical University, Tianjin 300070, China.
Department of Thoracic Surgery, Tianjin Chest Hospital, Tianjin 300222, China.
Cancers (Basel). 2025 Sep 5;17(17):2911. doi: 10.3390/cancers17172911.
: The circadian rhythm regulates important functions in the body, such as metabolism, the cell cycle, DNA repair, and immune balance. Disruption of this rhythm can contribute to the development of cancer. Circadian rhythm genes (CRGs) are attracting attention for their connection to various cancers. However, their roles in LUAD are not yet well understood. Additionally, our knowledge of how they function at both the bulk tissue and single-cell levels is limited. This gap hinders a complete understanding of how CRGs impact the development and outcomes of LUAD. : We selected 554 CRGs from public databases. We then obtained transcriptome data from TCGA and GEO. A total of 101 machine learning algorithm combinations were tested using 10 algorithms and 10-fold cross-validation. The best-performing model was based on Stepwise Cox regression and SuperPC. This model was validated with additional datasets. We also examined the relationships between CRGs, immune features, tumor mutation burden (TMB), and the response to immunotherapy. Drug sensitivity was also assessed. Single-cell data identified the cell types with active CRGs. Next, we performed qRT-PCR and other basic experiments to validate the expression of ARNTL2 in LUAD tissues and cell lines. The results indicated that ARNTL2 may play a key role in lung adenocarcinoma. : The CRG-based model clearly distinguished LUAD patients based on their risk. High-risk patients exhibited low immune activity, high TMB, and poor predicted responses to immunotherapy. Single-cell data revealed strong CRG signals in epithelial and fibroblast cells. These cell groups also displayed different communication patterns. Laboratory experiments showed that ARNTL2 was highly expressed in LUAD. It promoted cell growth, movement, and invasion. This suggests that ARNTL2 may play a role in promoting cancer. : This study developed a machine learning model based on CRGs. It can predict survival and immune status in LUAD patients. The research also identified ARNTL2 as a key gene that may contribute to cancer progression. These findings highlight the significance of the circadian rhythm in LUAD and provide new perspectives for diagnosis and treatment.
昼夜节律调节身体的重要功能，如新陈代谢、细胞周期、DNA修复和免疫平衡。这种节律的破坏会促使癌症的发展。昼夜节律基因（CRGs）因其与各种癌症的关联而受到关注。然而，它们在肺腺癌（LUAD）中的作用尚未得到充分了解。此外，我们对它们在大块组织和单细胞水平上如何发挥作用的认识有限。这一差距阻碍了对CRGs如何影响LUAD的发展和预后的全面理解。
我们从公共数据库中筛选出554个CRGs。然后，我们从TCGA和GEO获得了转录组数据。使用10种算法和10折交叉验证对总共101种机器学习算法组合进行了测试。表现最佳的模型基于逐步Cox回归和SuperPC。该模型用其他数据集进行了验证。我们还研究了CRGs、免疫特征、肿瘤突变负荷（TMB）和免疫治疗反应之间的关系。还评估了药物敏感性。单细胞数据确定了具有活跃CRGs的细胞类型。接下来，我们进行了qRT-PCR和其他基础实验，以验证ARNTL2在LUAD组织和细胞系中的表达。结果表明，ARNTL2可能在肺腺癌中起关键作用。
基于CRG的模型能够根据风险清晰地区分LUAD患者。高风险患者表现出低免疫活性、高TMB以及对免疫治疗的预测反应较差。单细胞数据显示上皮细胞和成纤维细胞中有强烈的CRG信号。这些细胞群也表现出不同的通讯模式。实验室实验表明，ARNTL2在LUAD中高表达。它促进细胞生长、运动和侵袭。这表明ARNTL2可能在促进癌症方面发挥作用。
本研究开发了一种基于CRGs的机器学习模型。它可以预测LUAD患者的生存和免疫状态。该研究还确定ARNTL2是一个可能促成癌症进展的关键基因。这些发现突出了昼夜节律在LUAD中的重要性，并为诊断和治疗提供了新的视角。
