Department of Physiology & Cell Biology, University of Health Sciences, Lahore, Pakistan.
Mol Biol Rep. 2014 Jan;41(1):95-103. doi: 10.1007/s11033-013-2841-7. Epub 2013 Nov 5.
Circadian rhythms are endogenous and self-sustained oscillations of multiple biological processes with approximately 24-h rhythmicity. Circadian genes and their protein products constitute the molecular components of the circadian oscillator that form positive/negative feedback loops and generate circadian rhythms. The circadian regulation extends from core clock genes to various clock-controlled genes that include various cell cycle genes. Aberrant expression of circadian clock genes, therefore, may lead to genomic instability and accelerated cellular proliferation potentially promoting carcinogenesis. The current study encompasses the investigation of simultaneous expression of four circadian clock genes (Bmal1, Clock, Per1 and Per2) and three clock-controlled cell cycle genes (Myc, Cyclin D1 and Wee1) at mRNA level and determination of serum melatonin levels in peripheral blood samples of 37 CLL (chronic lymphocytic leukemia) patients and equal number of age- and sex-matched healthy controls in order to indicate association between deregulated circadian clock and manifestation of CLL. Results showed significantly down-regulated expression of Bmal1, Per1, Per2 and Wee1 and significantly up-regulated expression of Myc and Cyclin D1 (P < 0.0001) in CLL patients as compared to healthy controls. When expression of these genes was compared between shift-workers and non-shift-workers within the CLL group, the expression was found more aberrant in shift-workers as compared to non-shift-workers. However, this difference was found statistically significant for Myc and Cyclin D1 only (P < 0.05). Serum melatonin levels were found significantly low (P < 0.0001) in CLL subjects as compared to healthy controls whereas melatonin levels were found still lower in shift-workers as compared to non-shift-workers within CLL group (P < 0.01). Our results suggest that aberrant expression of circadian clock genes can lead to aberrant expression of their downstream targets that are involved in cell proliferation and apoptosis and hence may result in manifestation of CLL. Moreover, shift-work and low melatonin levels may also contribute in etiology of CLL by further perturbing of circadian clock.
昼夜节律是生物过程的内源性和自我维持的振荡，大约具有 24 小时的节律性。昼夜节律基因及其蛋白质产物构成了昼夜节律振荡器的分子组成部分，形成正/负反馈回路并产生昼夜节律。昼夜节律的调节从核心时钟基因扩展到各种时钟控制基因，包括各种细胞周期基因。因此，昼夜节律基因的异常表达可能导致基因组不稳定和细胞增殖加速，从而潜在地促进致癌作用。本研究包括同时检测 37 例 CLL（慢性淋巴细胞白血病）患者和年龄、性别匹配的健康对照组外周血样本中 4 个昼夜节律钟基因（Bmal1、Clock、Per1 和 Per2）和 3 个时钟控制细胞周期基因（Myc、Cyclin D1 和 Wee1）的 mRNA 水平表达，并测定血清褪黑素水平，以指示失调的昼夜节律钟与 CLL 表现之间的关联。结果显示，与健康对照组相比，CLL 患者的 Bmal1、Per1、Per2 和 Wee1 表达显著下调，Myc 和 Cyclin D1 表达显著上调（P < 0.0001）。在 CLL 组中，比较移位工作者和非移位工作者之间这些基因的表达时，发现移位工作者的表达更为异常，而非移位工作者。然而，仅 Myc 和 Cyclin D1 的差异具有统计学意义（P < 0.05）。与健康对照组相比，CLL 患者的血清褪黑素水平明显降低（P < 0.0001），而在 CLL 组中，移位工作者的褪黑素水平仍然低于非移位工作者（P < 0.01）。我们的研究结果表明，昼夜节律基因的异常表达可导致其下游靶基因的异常表达，这些靶基因参与细胞增殖和凋亡，从而可能导致 CLL 的发生。此外，轮班工作和低褪黑素水平也可能通过进一步扰乱昼夜节律钟而导致 CLL 的发病机制。
