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 CLOCK, PER1, PER2, PER3, CRY1, CRY2, REV-ERBα, and RORα 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 CLOCK, CRY1, and RORα gene promoter regions were found to be methylated in cancer cells. Overexpression of CLOCK and PER2 in cancer cell lines inhibited cell proliferation and activation of RORα and REV-ERBα 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.

中文翻译：

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宫颈和食管癌细胞中的昼夜节律振荡持续存在，肿瘤抑制生物钟基因的表达降低

越来越多的证据表明生物钟紊乱与癌症进展之间存在联系。在这项研究中，对宫颈癌和食道癌的生物钟进行了研究，以确定它在这些癌症类型中是否被破坏。Oncomine 数据挖掘显示，与匹配的正常上皮相比，癌症患者组织中生物钟基因家族的多个成员下调。实时 RT-PCR 分析证实了食管肿瘤组织中 CLOCK、PER1、PER2、PER3、CRY1、CRY2、REV-ERBα 和 RORα 的显着下调。在细胞系模型中，与非癌症对照相比，转化细胞和癌细胞中几种生物钟基因的表达显着降低，并且蛋白质水平失调。这些效应至少部分是由甲基化介导的，其中 CLOCK、CRY1、和 RORα 基因启动子区域被发现在癌细胞中被甲基化。CLOCK 和 PER2 在癌细胞系中的过表达抑制细胞增殖，使用激动剂激活 RORα 和 REV-ERBα 导致癌细胞死亡，同时对正常上皮细胞的影响较小。尽管生物钟基因表达失调，宫颈癌细胞和食道癌细胞在地塞米松同步后仍保持功能性昼夜节律振荡，正如使用实时生物发光成像所揭示的那样，表明它们的生物钟机制是完整的。意义：这项研究首次描述了宫颈癌和食道癌细胞中失调但振荡的生物钟基因表达，并且对这些癌症类型中生物钟功能的了解有可能为时间疗法提供信息，