School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China.
Shenzhen Key Laboratory for Systemic Aging and Intervention, National Engineering Research Center for Biotechnology (Shenzhen), Medical Research Center, Shenzhen University Health Science Center, Shenzhen 518055, China.
Comput Math Methods Med. 2021 Oct 29;2021:8238833. doi: 10.1155/2021/8238833. eCollection 2021.
Hepatocellular carcinoma (HCC) is the leading cause of cancer-related mortality worldwide due to its asymptomatic onset and poor survival rate. This highlights the urgent need for developing novel diagnostic markers for early HCC detection. The circadian clock is important for maintaining cellular homeostasis and is tightly associated with key tumorigenesis-associated molecular events, suggesting the so-called chronotherapy. An analysis of these core circadian genes may lead to the discovery of biological markers signaling the onset of the disease. In this study, the possible functions of 13 core circadian clock genes (CCGs) in HCC were systematically analyzed with the aim of identifying ideal biomarkers and therapeutic targets. Profiles of HCC patients with clinical and gene expression data were downloaded from The Cancer Genome Atlas and International Cancer Genome Consortium. Various bioinformatics methods were used to investigate the roles of circadian clock genes in HCC tumorigenesis. We found that patients with high expression or low , , and expressions have poor survival. Besides, a prediction model consisting of these four CCGs, the tumor-node-metastasis (TNM) stage, and sex was constructed, demonstrating higher predictive accuracy than the traditional TNM-based model. In addition, pathway analysis showed that these four CCGs are involved in the cell cycle, PI3K/AKT pathway, and fatty acid metabolism. Furthermore, the network of these four CCGs-related coexpressed genes and immune infiltration was analyzed, which revealed the close association with B cells and nTreg cells. Notably, TIMELESS exhibited contrasting effects against CRY2, PER1, and RORA in most situations. In sum, our works revealed that these circadian clock genes , , , and can serve as potential diagnostic and prognostic biomarkers, as well as therapeutic targets, for HCC patients, which may promote HCC chronotherapy by rhythmically regulating drug sensitivity and key cellular signaling pathways.
肝细胞癌（HCC）是全球癌症相关死亡的主要原因，因为它起病隐匿，生存率低。这凸显了开发新型诊断标志物以早期发现 HCC 的迫切需求。生物钟对于维持细胞内稳态非常重要，并且与关键的肿瘤发生相关分子事件密切相关，提示所谓的时间治疗学。对这些核心生物钟基因的分析可能会发现预示疾病发生的生物标志物。在这项研究中，系统分析了 13 个核心生物钟基因（CCGs）在 HCC 中的可能功能，旨在确定理想的生物标志物和治疗靶点。从癌症基因组图谱和国际癌症基因组联盟下载了具有临床和基因表达数据的 HCC 患者的特征。使用各种生物信息学方法来研究生物钟基因在 HCC 肿瘤发生中的作用。我们发现，表达水平高或低的患者，其生存情况较差。此外，构建了一个由这四个 CCGs、肿瘤-淋巴结-转移（TNM）分期和性别组成的预测模型，其预测准确性高于传统的基于 TNM 的模型。此外，通路分析表明，这四个 CCGs 参与细胞周期、PI3K/AKT 通路和脂肪酸代谢。此外，还分析了这些四个 CCGs 相关共表达基因和免疫浸润的网络，这揭示了它们与 B 细胞和 nTreg 细胞的密切关联。值得注意的是，在大多数情况下，TIMLESS 对 CRY2、PER1 和 RORA 表现出相反的作用。总之，我们的研究结果表明，这些生物钟基因、、和可以作为潜在的诊断和预后生物标志物，以及治疗靶点，用于 HCC 患者，这可能通过节律性调节药物敏感性和关键细胞信号通路来促进 HCC 的时间治疗。
