Circadian disruption accelerates liver carcinogenesis in mice
Circadian disruption accelerates liver carcinogenesis in mice
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DOI：
10.1016/j.mrgentox.2009.10.002
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发表时间：
2009-11-01
影响因子：
1.9
通讯作者：
Levi, Francis
中科院分区：
文献类型：
--
作者：
Filipski, Elisabeth;Subramanian, Perumal;Levi, Francis
背景资料：昼夜节律计时系统在24小时内有节奏地控制行为、生理、细胞增殖和异生物质代谢。下丘脑中的视交叉上核通过一系列昼夜生理节律（包括休息-活动、体温、进食模式和激素分泌）来协调大多数哺乳动物细胞中的分子钟。因此，涉及昼夜节律破坏的轮班工作可能对人类致癌。在实验模型中，慢性时差反应（CJL）抑制了小鼠的静息活动和体温节律，并加速了两种可移植肿瘤的生长。CJL还抑制或显著改变肝脏和肿瘤中时钟基因的表达节律。来自CJL的昼夜节律钟破坏下调p53并上调c-Myc，从而有利于细胞增殖。在这里，我们研究了CJL作为肿瘤促进剂在暴露于肝致癌物二乙基亚硝胺（DEN）的小鼠中的作用。在小鼠中探索DEN的施用。在实验2中，小鼠接受10 mg/kg/天的DEN（累积剂量：243 mg/kg），然后随机保持在光周期方案中，其中12小时的光照与12小时的黑暗交替（LD 12：12）或提交给CJL（每2天提前8小时光照）。监测静息活动和体温。重复测定血清肝酶。结果：在实验1中，DEN 10 mg/kg/day组小鼠全部发生肝癌。在实验2中，与LD小鼠相比，CJL组小鼠的天冬氨酸转氨酶平均血浆水平升高，肝脏肿瘤更多，相似于10个月（分别为p = 0.005和0.028）。CJL小鼠最大肝肿瘤的平均直径是LD小鼠的两倍（8.5 vs 4.4 mm，p = 0.027）。在LD中，观察到每个肝脏的单一组织学肿瘤类型。在CJL中，多达四种不同的类型与同一肝脏相关（肝细胞癌或胆管癌，肉瘤或混合瘤）。DEN本身明显扰乱了所有小鼠的休息-活动和体温的昼夜节律。DEN诱导的破坏延长>= 3个月CJL exposation.Conclusions：昼夜节律的破坏与慢性DEN暴露的关联表明，生物钟积极控制小鼠肝癌发生的机制。持续的昼夜节律协调可能进一步对致癌物暴露后减缓和/或逆转癌症发展至关重要。(C)2009爱思唯尔有限公司版权所有。
Background: The circadian timing system rhythmically controls behavior, physiology, cellular proliferation and xenobiotic metabolism over the 24-h period. The suprachiasmatic nuclei in the hypothalamus coordinate the molecular clocks in most mammalian cells through an array of circadian physiological rhythms including rest-activity, body temperature, feeding patterns and hormonal secretions. As a result, shift work that involves circadian disruption is probably carcinogenic in humans. In experimental models, chronic jet-lag (CJL) suppresses rest-activity and body temperature rhythms and accelerates growth of two transplantable tumors in mice. CJL also suppresses or significantly alters the expression rhythms of clock genes in liver and tumors. Circadian clock disruption from CJL downregulates p53 and upregulates c-Myc, thus favoring cellular proliferation. Here, we investigate the role of CJL as a tumor promoter in mice exposed to the hepatic carcinogen, diethylnitrosamine (DEN).Methods: In experiment 1 (Exp 1), the dose-dependent carcinogenicity of chronic intraperitoneal (i.p.) administration of DEN was explored in mice. In Exp 2, mice received DEN at 10 mg/kg/day (cumulative dose: 243 mg/kg), then were randomized to remain in a photoperiodic regimen where 12 h of light alternates with 12 h of darkness (LD 12:12) or to be submitted to CJL(8-h advance of light onset every 2 days). Rest-activity and body temperature were monitored. Serum liver enzymes were determined repeatedly. Mice were sacrificed and examined for neoplastic lesions at 10 months.Results: In Exp 1, DEN produced liver cancers in all the mice receiving 10 mg/kg/day. In Exp 2, mice on CJL had increased mean plasma levels of aspartate aminotransferase and more liver tumors as compared to LD mice at similar to 10 months (p = 0.005 and 0.028, respectively). The mean diameter of the largest liver tumor was twice as large in CJL vs LD mice (8.5 vs 4.4 mm, p = 0.027). In LD, a single histologic tumor type per liver was observed. In CJL, up to four different types were associated in the same liver (hepatocellular-or cholangio-carcinomas, sarcomas or mixed tumors). DEN itself markedly disrupted the circadian rhythms in rest-activity and body temperature in all the mice. DEN-induced disruption was prolonged for >= 3 months by CJL exposure.Conclusions: The association of circadian disruption with chronic DEN exposure suggests that circadian clocks actively control the mechanisms of liver carcinogenesis in mice. Persistent circadian coordination may further be critical for slowing down and/or reverting cancer development after carcinogen exposure. (C) 2009 Elsevier B.V. All rights reserved.