TIMELESS as a prognostic biomarker and therapeutic target in gastric cancer

Abstract

Background: Gastric cancer (GC), one of the most prevalent malignancies worldwide, is characterized by complex etiological and pathological mechanisms. Emerging evidence on the dysregulation of circadian clock genes has revealed promising opportunities for improving the diagnosis, treatment, and prognosis of patients with GC. Methods: This study utilized a multifaceted approach combining machine learning algorithms, gene set enrichment analysis, immune infiltration profiling, survival prognosis analysis, drug sensitivity testing, and in vitro experiments to investigate the functional roles of core clock genes in GC. Results: By integrating data from The Cancer Genome Atlas, Gene Expression Omnibus datasets, and the National Center for Biotechnology Information database, we identified 29 differentially expressed clock genes in GC. Among these, the application of four distinct machine learning algorithms highlighted TIMELESS (TIM) and BHLHE41 as pivotal genes, with TIM demonstrating notable diagnostic performance (area under the receiver operating characteristic curve = 0.802). Elevated TIM expression was strongly associated with poor clinical prognosis and increased infiltration of immune cells in tumor tissues. Notably, a specific interaction was identified between TIM and the pyroptosis-associated molecule CASP8, indicating a potential synergistic role in GC pathogenesis. Additionally, bortezomib emerged as a potential targeted therapeutic agent capable of modulating TIM activity in GC. Conclusion: TIM is identified as a promising diagnostic biomarker and therapeutic target in GC, offering valuable implications for improving patient prognosis and guiding personalized treatment strategies.

Keywords

• TIMELESS
• Gastric cancer
• Prognosis
• Tumor-infiltrating
• Pyroptosis
• Clock gene