School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen 518000, China.
Bacteriology & Antibacterial Resistance Surveillance Laboratory, Shenzhen Institute of Respiratory Diseases, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, Shenzhen 518020, China.
Biomed Res Int. 2022 Jul 4;2022:9774879. doi: 10.1155/2022/9774879. eCollection 2022.
Gliomas are the most common primary intracranial tumors and closely related to circadian clock. Due to the high mortality and morbidity of gliomas, exploring novel diagnostic and early prognostic markers is necessary. Circadian clock genes (CCGs) play important roles in regulating the daily oscillation of biological processes and the development of tumor. Therefore, we explored the influences that the oscillations of circadian clock genes (CCGs) on diagnosis and prognosis of gliomas using bioinformatics. In this work, we systematically analyzed the rhythmic expression of CCGs in brain and found that some CCGs had strong rhythmic expression; the expression levels were significantly different between day and night. Four CCGs (, , , and ) with rhythmic expression were not only identified as differentially expressed genes but also had significant independent prognostic ability in the overall survival of glioma patients and were highly correlated with glioma prognosis in COX analysis. Besides, we found that CCG-based predictive model demonstrated higher predictive accuracy than that of the traditional grade-based model; this new prediction model can greatly improve the accuracy of glioma prognosis. Importantly, based on the four CCGs' circadian oscillations, we revealed that patients sampled at night had higher predictive ability. This may help detect glioma as early as possible, leading to early cancer intervention. In addition, we explored the mechanism of CCGs affecting the prognosis of glioma. CCGs regulated the cell cycle, DNA damage, Wnt, mTOR, and MAPK signaling pathways. In addition, it also affects prognosis through gene coexpression and immune infiltration. Importantly, can rhythmically modulated the cellular sensitivity to clinic drugs, temozolomide. The optimal point of temozolomide administration should be when expression is highest, that is, the effect is better at night. In summary, our study provided a basis for optimizing clinical dosing regimens and chronotherapy for glioma. The four key CCGs can serve as potential diagnostic and prognostic biomarkers for glioma patients, and also has obvious advantages in the direction of glioma chronotherapy.
神经胶质瘤是最常见的原发性颅内肿瘤，与生物钟密切相关。由于神经胶质瘤的高死亡率和发病率，探索新的诊断和早期预后标志物是必要的。生物钟基因（CCGs）在调节生物过程的日常波动和肿瘤的发展中起着重要作用。因此，我们使用生物信息学方法探索了生物钟基因（CCGs）的波动对神经胶质瘤诊断和预后的影响。在这项工作中，我们系统地分析了 CCG 在大脑中的节律表达，发现一些 CCG 具有很强的节律表达；昼夜之间的表达水平有显著差异。具有节律表达的四个 CCG（，，，和）不仅被鉴定为差异表达基因，而且在神经胶质瘤患者的总生存中具有显著的独立预后能力，并且在 COX 分析中与神经胶质瘤预后高度相关。此外，我们发现基于 CCG 的预测模型比传统的分级模型具有更高的预测准确性；这种新的预测模型可以大大提高神经胶质瘤预后的准确性。重要的是，基于四个 CCG 的昼夜波动，我们发现夜间取样的患者具有更高的预测能力。这可能有助于尽早发现神经胶质瘤，从而尽早进行癌症干预。此外，我们还探讨了 CCG 影响神经胶质瘤预后的机制。CCGs 调节细胞周期、DNA 损伤、Wnt、mTOR 和 MAPK 信号通路。此外，它还通过基因共表达和免疫浸润影响预后。重要的是，可以节律性地调节细胞对临床药物替莫唑胺的敏感性。替莫唑胺给药的最佳时间点应该是 表达最高的时候，即夜间效果更好。总之，我们的研究为优化神经胶质瘤的临床给药方案和时间治疗提供了依据。这四个关键的 CCG 可以作为神经胶质瘤患者潜在的诊断和预后生物标志物，而 在神经胶质瘤时间治疗方向上也具有明显优势。
