BACKGROUND: Circadian rhythms govern a wide range of physiological processes essential for cellular homeostasis, such as cell cycle progression, DNA repair, metabolism, and apoptosis. Disruptions to these rhythms are linked to cancer initiation, progression, and therapy response. While the role of circadian genes in cancer cells has been well-documented, their impact on the tumor microenvironment (TME), particularly in endothelial cells, remains underexplored. This study investigates the dysregulation of circadian rhythm-related genes in endothelial cells across multiple cancers and their clinical significance.
METHODS: We conducted a pan-cancer analysis using single-cell RNA sequencing data from the Tumor Immune Single-cell Hub database. A total of 15 independent datasets were analyzed, involving rigorous data processing steps, such as filtering, quality control, and cell type identification. Circadian rhythm activity was quantified using circadian rhythm scores, and genes with elevated expression in endothelial cells were identified. The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) datasets were employed for prognostic analysis. A risk model based on circadian rhythm-related genes was developed using LASSO regression, with validation across multiple independent cohorts.
RESULTS: Our analysis revealed that endothelial cells exhibited consistently high circadian rhythm scores, highlighting their crucial role in regulating circadian rhythms within the TME. We identified a gene signature, ENDO.CIRCADIAN.RHYTHM.SIG , consisting of 101 genes positively correlated with endothelial cell-specific circadian rhythms. Dysregulation of these genes was prevalent across various cancer types and correlated with poor prognosis, with specific genes like ITGA5, SLC2A3 , and SERPINE1 identified as potential risk factors. Kaplan-Meier survival analysis indicated that higher expression of these genes was associated with decreased overall survival. The correlation of ENDO.CIRCADIAN.RHYTHM.SIG expression with immune infiltration and stromal components suggested that endothelial circadian rhythms modulate key aspects of the TME. Notably, the circadian rhythm gene set was significantly associated with angiogenesis and inflammatory pathways, especially in liver hepatocellular carcinoma (LIHC). A prognostic risk model for breast cancer (BRCA) based on these genes showed robust predictive performance.
CONCLUSION: Endothelial circadian rhythm genes play a significant role in regulating tumor progression, immune interactions, and patient prognosis. Dysregulation of the ENDO.CIRCADIAN.RHYTHM.SIG gene set correlates with adverse clinical outcomes and may serve as a potential prognostic biomarker and therapeutic target. Our findings suggest that targeting circadian rhythm pathways within the TME could enhance personalized cancer treatment strategies.
