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

Abstract

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, RevErba 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-Erba 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-Erba 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 genespecific 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.

The circadian clock gene PER2 plays an important role in tumor suppression through regulating tumor-associated genes in human oral squamous cell carcinoma

“…Recent studies have revealed that clock gene PER2 is reduced in various types of solid cancers, such as breast cancer, prostate cancer, and colorectal cancer (1,14,20,24), and PER2 can regulate downstream many cell cycle genes, such as CyclinA, CyclinB1, CyclinD1, and CyclinE; therefore, PER2 downregulation can lead to the process change of cell cycle, promote the growth of cancer cells, and inhibit apoptosis (27,29). Our previous research also proved that PER2 expression was reduced in human OSCC cells through the regulation of the downstream cell cycle gene, sequentially, which is closely related to the occurrence of cancers (30).…”

“…PER2 is reduced in various types of cancer cells, including breast cancer, neck squamous cell carcinoma, prostate cancer, colorectal cancer, hepatocellular carcinoma, skin cancer, gastric cancer, and myeloid leukemia (1,10,14,(20)(21)(22)(23)(24)(25)(26). PER2 can regulate downstream plentiful cell cycle genes, such as CyclinA, CyclinB1, CyclinD1, CyclinE, p53, and C-myc (14,(27)(28)(29).…”

Circadian rhythms and new options for novel anticancer therapies

“…59,60 All of the foregoing show that functional circadian clock might operate as a tumor suppressor. 61 Further evidence that circadian clock is disrupted in cancer is shown in the study of Soták et al: 61 the expression profile of Dbp had robust circadian rhythmicity in the colonic mucosa of healthy mice and in the surrounding nonneoplastic tissue of tumor-bearing mice, but the amplitude of the tumors was reduced, and the amplitude was delayed. The rhythmic expression of core clock genes was markedly reduced in comparison with surrounding nonneoplastic tissue, and even more in comparison with colon mucosa of healthy animals.…”

The tumor circadian clock: a new target for cancer therapy?

“…For example, in mice with lung adenocarcinoma, circadian gene expression was largely affected in the liver, with many genes losing rhythmicity, others becoming rhythmic, and some being shifted earlier or later [15]. In humans, alterations in clock gene expression and consequently clock-controlled gene expression was documented in the healthy gut tissues surrounding the tumor [18,19].…”

“…Notably, recent evidence indicates a significant reduction of circadian rhythmicity restricted to murine colon tumor tissue, whereas rhythms were unchanged in healthy colon tissue surrounding the tumor [19]. In fact, the intratumoral circadian disruption correlates with the patient's prognosis and survival [17,18].…”