Pan‐cancer analyses reveal genomics and clinical characteristics of the melatonergic regulators in cancer
Pan‐cancer analyses reveal genomics and clinical characteristics of the melatonergic regulators in cancer
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DOI：
10.1111/jpi.12758
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发表时间：
2021-07
影响因子：
10.3
通讯作者：
Jian Zhang;Huali Jiang;Kunpeng Du;T. Xie;Baiyao Wang;Chengcong Chen;R. Reiter;B. Cen;Yawei Yuan
中科院分区：
文献类型：
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作者：
Jian Zhang;Huali Jiang;Kunpeng Du;T. Xie;Baiyao Wang;Chengcong Chen;R. Reiter;B. Cen;Yawei Yuan
褪黑激素是一种内源性激素，在癌症中起保护作用。除了调节昼夜节律，睡眠和神经内分泌活动，褪黑激素在各种生存途径中发挥作用。然而，褪黑激素在癌症中的调节机制仍然未知。在本研究中，我们使用来自癌症基因组图谱和癌细胞系百科全书的多组学数据对33种癌症类型的9125个肿瘤样本中的褪黑激素调节剂进行了全面表征。在基因组图谱中，我们确定AANAT和GPR 50的杂合扩增以及PER 3、CYP 2C 19和MTNR 1A的杂合缺失为显性改变事件。表达分析显示甲基化介导的褪黑激素能调节因子表达下调。此外，我们发现褪黑激素能调节因子的表达可用于预测各种癌症患者的生存率。microRNA（miRNA）分析揭示了一个miRNA-mRNA相互作用网络，并且去调控的miRNAs通过靶向生物钟基因参与褪黑激素的分泌和代谢。通路分析表明，褪黑激素能调节剂与抑制细胞凋亡，细胞周期，DNA损伤反应，激活RAS/MAPK和RTK信号通路。重要的是，通过挖掘癌症药物敏感性基因组数据库，我们发现了一些可能靶向褪黑激素调节剂的潜在药物。总之，本研究揭示了33种癌症中褪黑素能调节因子的基因组改变和临床特征，这可能阐明褪黑素与肿瘤发生的关系。我们的发现也可能为癌症的临床治疗提供新的方法。
Melatonin, an endogenous hormone, plays protective roles in cancer. In addition to regulating circadian rhythms, sleep, and neuroendocrine activity, melatonin functions in various survival pathways. However, the mechanisms of melatonin regulation in cancer remain unknown. In the present study, we performed a comprehensive characterization of melatonin regulators in 9125 tumor samples across 33 cancer types using multi‐omic data from The Cancer Genome Atlas and Cancer Cell Line Encyclopedia. In the genomic landscape, we identified the heterozygous amplification of AANAT and GPR50, and heterozygous deletion of PER3, CYP2C19, and MTNR1A as the dominant alteration events. Expression analysis revealed methylation‐mediated downregulation of melatonergic regulator expression. In addition, we found that melatonergic regulator expression could be used to predict patient survival in various cancers. In depth, microRNA (miRNA) analysis revealed an miRNA‐mRNA interaction network, and the deregulated miRNAs were involved in melatonin secretion and metabolism by targeting circadian clock genes. Pathway analysis showed that melatonergic regulators were associated with inhibition of apoptosis, the cell cycle, the DNA damage response, and activation of RAS/MAPK and RTK signaling pathways. Importantly, by mining the Genomics of Drug Sensitivity in Cancer database, we discovered a number of potential drugs that might target melatonergic regulators. In summary, this study revealed the genomic alteration and clinical characteristics of melatonergic regulators across 33 cancers, which might clarify the relationship between melatonin and tumorigenesis. Our findings also might provide a novel approach for the clinical treatment of cancers.