Division of Medical Biochemistry and Structural Biology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
School of Life Sciences, Coventry University, Coventry, United Kingdom.
Mol Cancer Res. 2020 Sep;18(9):1340-1353. doi: 10.1158/1541-7786.MCR-19-1074. Epub 2020 Jun 5.
There is accumulating evidence for a link between circadian clock disruption and cancer progression. In this study, the circadian clock was investigated in cervical and esophageal cancers, to determine whether it is disrupted in these cancer types. Oncomine datamining revealed downregulation of multiple members of the circadian clock gene family in cancer patient tissue compared with matched normal epithelium. Real-time RT-PCR analysis confirmed significant downregulation of α, and α in esophageal tumor tissue. In cell line models, expression of several circadian clock genes was significantly decreased in transformed and cancer cells compared with noncancer controls, and protein levels were dysregulated. These effects were mediated, at least in part, by methylation, where , and α gene promoter regions were found to be methylated in cancer cells. Overexpression of and in cancer cell lines inhibited cell proliferation and activation of α and α using agonists resulted in cancer cell death, while having a lesser effect on normal epithelial cells. Despite dysregulated circadian clock gene expression, cervical and esophageal cancer cells maintain functional circadian oscillations after Dexamethasone synchronization, as revealed using real-time bioluminescence imaging, suggesting that their circadian clock mechanisms are intact. IMPLICATIONS: This study is a first to describe dysregulated, yet oscillating, circadian clock gene expression in cervical and esophageal cancer cells, and knowledge of circadian clock functioning in these cancer types has the potential to inform chronotherapy approaches, where the timing of administration of chemotherapy is optimized on the basis of the circadian clock.
越来越多的证据表明，生物钟紊乱与癌症的进展有关。在这项研究中，研究了宫颈癌和食管癌中的生物钟，以确定这些癌症类型中是否存在生物钟紊乱。Oncomine 数据分析显示，与匹配的正常上皮组织相比，癌症患者组织中多个生物钟基因家族成员的表达下调。实时 RT-PCR 分析证实，食管肿瘤组织中α和α的表达显著下调。在细胞系模型中，与非癌细胞对照相比，转化细胞和癌细胞中几种生物钟基因的表达显著降低，且蛋白水平失调。这些影响至少部分是通过甲基化介导的，其中发现癌症细胞中的和α基因启动子区域被甲基化。在癌细胞系中过表达和可抑制癌细胞增殖，并用激动剂激活α和α可导致癌细胞死亡，而对正常上皮细胞的影响较小。尽管生物钟基因表达失调，但宫颈癌和食管癌细胞在 Dexamethasone 同步后仍保持功能性生物钟振荡，如实时生物发光成像所示，表明它们的生物钟机制完整。意义：这项研究首次描述了宫颈癌和食管癌细胞中生物钟基因表达失调但仍存在振荡，了解这些癌症类型中的生物钟功能有可能为时间治疗方法提供信息，即根据生物钟优化化疗的给药时间。
