Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.
Clinic Medicine of 5-year Program, Xiangya School of Medicine, Central South University, Changsha, China.
Cell Prolif. 2021 Mar;54(3):e12988. doi: 10.1111/cpr.12988. Epub 2021 Jan 13.
Circadian rhythm controls complicated physiological activities in organisms. Circadian clock genes have been related to tumour progression, but its role in glioma is unknown. Therefore, we explored the relationship between dysregulated circadian clock genes and glioma progression.
Samples were divided into different groups based on circadian clock gene expression in training dataset (n = 672) and we verified the results in other four validating datasets (n = 1570). The GO and GSEA enrichment analysis were conducted to explore potential mechanism of how circadian clock genes affected glioma progression. The single-cell RNA-Seq analysis was conducted to verified previous results. The immune landscape was evaluated by the ssGSEA and CIBERSORT algorithm. Cell proliferation and viability were confirmed by the CCK8 assay, colony-forming assay and flow cytometry.
The cluster and risk model based on circadian clock gene expression can predict survival outcome. Samples were scoring by the least absolute shrinkage and selection operator regression analysis, and high scoring tumour was associated with worse survival outcome. Samples in high-risk group manifested higher activation of immune pathway and cell cycle. Tumour immune landscape suggested high-risk tumour infiltrated more immunocytes and more sensitivity to immunotherapy. Interfering TIMELESS expression affected circadian clock gene expression, inhibited tumour cell proliferation and arrested cell cycle at the G0/G1 phase.
Dysregulated circadian clock gene expression can affect glioma progression by affecting tumour immune landscape and cell cycle. The risk model can predict glioma survival outcome, and this model can also be applied to pan-cancer.
昼夜节律控制着生物体复杂的生理活动。昼夜节律基因与肿瘤进展有关，但在神经胶质瘤中的作用尚不清楚。因此，我们探讨了失调的昼夜节律基因与神经胶质瘤进展之间的关系。
根据训练数据集（n=672）中昼夜节律基因表达将样本分为不同组，然后在另外四个验证数据集（n=1570）中验证结果。进行 GO 和 GSEA 富集分析，以探讨昼夜节律基因影响神经胶质瘤进展的潜在机制。进行单细胞 RNA-Seq 分析以验证之前的结果。通过 ssGSEA 和 CIBERSORT 算法评估免疫图谱。通过 CCK8 测定、集落形成测定和流式细胞术确认细胞增殖和活力。
基于昼夜节律基因表达的聚类和风险模型可预测生存结局。通过最小绝对收缩和选择算子回归分析对样本进行评分，高评分肿瘤与较差的生存结局相关。高风险组样本表现出更高的免疫途径和细胞周期激活。肿瘤免疫图谱表明高风险肿瘤浸润更多免疫细胞，对免疫治疗更敏感。干扰 TIMESLESS 表达会影响昼夜节律基因表达，抑制肿瘤细胞增殖并将细胞周期阻滞在 G0/G1 期。
昼夜节律基因表达失调可通过影响肿瘤免疫图谱和细胞周期来影响神经胶质瘤的进展。该风险模型可预测神经胶质瘤的生存结局，并且该模型也可应用于泛癌症。
