An association between clock genes and clock‐controlled cell cycle genes in murine colorectal tumors

Disruption of circadian machinery appears to be associated with the acceleration of tumor development. To evaluate the function of the circadian clock during neoplastic transformation, the daily profiles of the core clock genes Per1, Per2, Rev‐Erbα and Bmal1, the clock‐controlled gene Dbp and the clock‐controlled cell cycle genes Wee1, c‐Myc and p21 were detected by real‐time RT‐PCR in chemically induced primary colorectal tumors, the surrounding normal tissue and in the liver. The circadian rhythmicity of Per1, Per2, Rev‐Erbα and Dbp was significantly reduced in tumor compared with healthy colon and the rhythmicity of Bmal1 was completely abolished. Interestingly, the circadian expression of Per1, Per2, Rev‐Erbα and Dbp persisted in the colonic tissue surrounding the tumor but the rhythmic expression of Bmal1 was also abolished. Daily profiles of Wee1, c‐Myc and p21 did not exhibit any rhythmicity either in tumors or in the colon of healthy animals. The absence of diurnal rhythmicity of cell cycle genes was partially associated with ageing, because young healthy mice showed rhythmicity in the core clock genes as well as in the Wee1 and p21. In the liver of tumor‐bearing mice the clock gene rhythms were temporally shifted. The data suggest that the circadian regulation is distorted in colonic neoplastic tissue and that the gene‐specific disruption may be also observed in the non‐neoplastic tissues. These findings reinforce the role of peripheral circadian clockwork disruption for carcinogenesis and tumor progression. What's new? Epidemiological and molecular studies have established intriguing links between the circadian rhythm and cancer. In this study, the authors monitored expression of key genes involved in the mammalian circadian clock in a mouse colon cancer model. They find disruptions of circadian homeostasis not only in colonic tumor cells, but also in surrounding colonic tissue as well as in other tissues, specifically in the liver. These results demonstrate a wide‐spread loss of clock function and allow speculations into causal interactions between dysregulated clock‐gene expression and colon tumor development.