Molecular clock mechanism of cancer

虽然昼夜节律的改变被认为增加了癌症的风险，但生物钟与肿瘤发生之间的关系尚未阐明。首先，我们建立了二乙基亚硝胺(DEN)诱导的大鼠肝肿瘤模型。DEN(80 mg/L或160 mg/L)组大鼠出现肝细胞癌，而DEN(40 mg/L)组大鼠未见肝癌。体重从DEN早期(160 mg/L)开始急剧下降，出现死亡病例。根据这些结果，我们确定DEN的浓度为80 mg/L，以诱发大鼠肝脏肿瘤。其次，我们研究了DEN对大鼠肝脏时钟基因、mRNA和蛋白质24小时节律的影响。对照组大鼠肝脏Clock、BMal1、PER1、PER2和Cry1基因的表达存在明显的24小时节律(P&lt；0.05)。在DEN处理组，肝脏Clock、BMal1、PER2和Cry1mRNA的表达水平呈现明显的24小时节律…更多(分别为P&lt；0.05)。但PER1的mRNA水平无24小时节律。此外，DEN治疗组小鼠肝脏Clock、PER1、PER2和Cry1基因的表达水平均低于对照组。DEN导致每个节律的低幅度和/或相移。BMal1mRNA在肝脏中的表达幅度与对照组相同。对照组大鼠肝脏Clock蛋白表达无节律性。DEN处理组的Clock蛋白表达低于对照组。对照组大鼠肝脏PER2蛋白表达呈24小时节律。DEN处理组PER2蛋白表达低于对照组。在本研究中，长期给予DEN诱发了大鼠肝脏肿瘤，并改变了时钟基因及其蛋白水平的24小时节律。此外，据报道，外科手术切除SCN会扰乱昼夜节律，从而加速肿瘤的进展。因此，Clock基因24小时节律的改变被认为在肿瘤发生过程中具有重要意义。较少

Although the alteration of circadian rhythm is suggested to increase the risk of cancer, the relationship between the circadian clock and tumorigenesis has not been clarified. Firstly, we constructed the liver tumor induced by Diethylnitrosamine (DEN) in rats. Hepatocellular carcinoma (HCC) were found in rats administered with DEN (80 mg/l or 160 mg/l), but there was no HCC in rats administered with DEN (40 mg/l). Body weight decreased strongly from the early stage of DEN (160 mg/l) and showed the case of death. From these results, we decided concentration of DEN at 80 mg/l to induce tumor in rat liver. Secondly, we investigated the influence of DEN on the 24-hr rhythm of clock genes mRNA and proteins in rats liver. In the control group, the mRNA levels of Clock, Bmal1,Per1,Per2 and Cry1 in the liver showed a significant 24-hr trhythm (P<0.05,respectively). In DEN treated group, the mRNA levels of Clock, Bmal1,Per2 and Cry1 mRNA expression in the liver showed a significant 24-hr rhythm … More (P<0.05,respectively). But, the mRNA level of Per1 showed no 24-hr rhythm. Moreover, the mRNA levels of Clock,Per1,Per2 and Cry1 in the liver was lower in DEN treated group than control group. DEN caused a low amplitude and/or a phase shift of each rhythm. Bmal1 mRNA expression in the liver showed the same amplitude as control group. In control group, CLOCK protein expression in the liver showed no rhythmic expression. CLOCK protein expression was lower in DEN treated group than control group. In control group, PER2 protein expression in the liver showed 24-hr rhythm. PER2 protein expression was lower in DEN treated group than control group. In the present study, the chronic administration of DEN induced liver tumor in rats, and altered the 24-hr rhythm of clock genes and their protein levels. Also, circadian disruption by surgical ablation of the SCN is reported to accelerate tumor progression. Therefore, the alteration of the 24-hr rhythm of clock gene is considered to be important in the process of tumorigenesis. Less