Clock Genes and Cancer
Clock Genes and Cancer
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DOI：
10.1177/1534735409355292
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发表时间：
2009-12-01
影响因子：
2.9
通讯作者：
Hrushesky, William J. M.
中科院分区：
文献类型：
--
作者：
Wood, Patricia A.;Yang, Xiaoming;Hrushesky, William J. M.
周期基因(PER2、PER1)是重要的生物钟基因。它们还起到负增长调节器的作用。PER2突变小鼠表现出从头开始和辐射诱导的上皮增生、肿瘤和异常的DNA损伤反应。人类肿瘤表现为周期性基因突变或表达降低。其他小鼠时钟基因突变与肿瘤易感表型无关。轮班工作和夜间光线暴露与生物钟扰乱和癌症风险增加有关。生物钟和癌症之间的联系的机制还没有很好的定义。我们认为，昼夜节律干扰本身并不是一致的促癌作用，特定的昼夜节律干扰促进肿瘤的机制将取决于所涉及的基因和途径。我们认为周期时钟基因突变通过独特的分子途径促进肿瘤的发生。PER2和PER1调节结肠癌和非结肠癌细胞中的β-连环蛋白和细胞增殖。PER2突变增加了肠道β-连环素水平和结肠息肉的形成。PER2突变也增加了APC(Min/+)介导的肠和结肠息肉形成。肠道肿瘤本身也可能由于β-连环蛋白破坏PER2蛋白的稳定而改变时钟功能。APC(Min/+)小鼠肠道PER2表达水平和昼夜节律显著降低，肠道时钟基因和时钟调控基因表达出现选择性异常。我们认为，由于β-连环蛋白信号和DNA损伤反应的改变，通过丢失周期时钟蛋白来促进肿瘤是这些时钟基因所特有的。周期蛋白可能为癌症预防和控制提供新的靶点。
Period genes (Per2, Per1) are essential circadian clock genes. They also function as negative growth regulators. Per2 mutant mice show de novo and radiation-induced epithelial hyperplasia, tumors, and an abnormal DNA damage response. Human tumors show Period gene mutations or decreased expression. Other murine clock gene mutations are not associated with a tumor prone phenotype. Shift work and nocturnal light exposure are associated with circadian clock disruption and with increased cancer risk. The mechanisms responsible for the connection between the circadian clock and cancer are not well defined. We propose that circadian disruption per se is not uniformly tumor promoting and the mechanisms for tumor promotion by specific circadian clock disturbances will differ dependent upon the genes and pathways involved. We propose that Period clock gene mutations promote tumorigenesis by unique molecular pathways. Per2 and Per1 modulate beta-catenin and cell proliferation in colon and non-colon cancer cells. Per2 mutation increases intestinal beta-catenin levels and colon polyp formation. Per2 mutation also increases Apc(Min/+)-mediated intestinal and colonic polyp formation. Intestinal tumorigenesis per se may also alter clock function as a result of increased beta-catenin destabilizing PER2 protein. Levels and circadian rhythm of PER2 in Apc(Min/+) mouse intestine are markedly decreased, and selective abnormalities in intestinal clock gene and clock-controlled gene expression are seen. We propose that tumor promotion by loss of PERIOD clock proteins is unique to these clock genes as a result of altered beta-catenin signaling and DNA damage response. PERIOD proteins may offer new targets for cancer prevention and control.