Molecular clock mechanism of cancer

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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