Expression of circadian clock genes in human colorectal adenoma and carcinoma

Abstract

Circadian rhythms are fundamental biological systems in most organisms. Epidemiological and animal studies have demonstrated that disruption of circadian rhythms is linked to tumor progression and mammalian tumorigenesis. However, the clinical significance of in situ clock gene expression in precancerous and cancerous colorectal lesions remains unknown. The present study aimed to investigate mRNA transcript levels of circadian clock genes within human colorectal cancer and adenoma tissue sections. Using in situ hybridization, the expression of key clock genes, including period circadian protein homolog (Per) 1 and 2, cryptochrome 1 (Cry1), circadian locomoter output cycles protein kaput (Clock), brain and muscle ARNT-like protein 1 (Bmal1) and casein kinase 1ε (CK1ε) were retrospectively examined in 51 cases of colorectal carcinoma and 10 cases of adenoma. The expression of clock genes was almost undetectable in the majority of adenomas, whereas positive expression of clock genes was observed in 27–47% of carcinomas. Notably, positive Per1, Per2 and Clock staining in colorectal carcinomas were each significantly associated with a larger tumor size (P=0.012, P=0.011 and P=0.009, respectively). Tumors with positive Per2 and Clock expression tended to exhibit deeper depth of invasion and were generally more advanced than tumors that did not express these genes (P=0.052 and P=0.064, respectively). However, no statistically significant association was observed between clock gene expression and clinicopathological variables, including histopathological differentiation, lymph node metastasis, depth of invasion or disease stage, although Per2-positive tumors tended to be associated with poorer overall survival (P=0.060). The results of the current study suggest that dysregulated expression of clock genes may be important in human colorectal tumorigenesis.

RETRACTED: Melatonin modulates dysregulated circadian clocks in mice with diethylnitrosamine‐induced hepatocellular carcinoma

“…In the current study, CK1ε was downregulated in DEN‐treated mice, as it occurred with Per and Cry, while Bmal1, Clock, and Npas2 genes were upregulated. These data are in agreement with previous research which has shown a changed expression of CK1ε in parallel to the disrupted profile of other circadian clock genes in gastric cancer or human colorectal carcinoma . Melatonin treatment resulted in a CK1ε upregulation that could contribute to its protective effect.…”

Mutation of the gene encoding the circadian clock component PERIOD2 in oncogenic cells confers chemoresistance by up-regulating the Aldh3a1 gene

“…The retrospective analysis of patients with breast cancer also indicates that low expression of PER2 is associated with poor prognosis. The role of clock genes in controlling the sensitivity of cancer cells to chemotherapeutic drugs has been demonstrated by the overexpression of Bmal1 (39), loss of Cry1/2 (40), and down-regulation of Per2 (41). The modulation of chemosensitivity of cancer cells by clock genes is closely related to their ability to regulate cell-cycle progression and apoptosis.…”

Clock genes alterations and endocrine disorders

“…127 In vivo and in vitro studies have demonstrated that disruption of circadian rhythms is linked to tumour progression and mammalian tumorigenesis for several malignancies such as liver cancer, 128 oral squamous cell carcinoma, 129 gastric, pancreatic and colorectal carcinoma. 130 Clock genes contribute to the occurrence and development of tumours by regulating and interfering with oncogenes (c-myc), tumoursuppressor genes (P53 and P21), genes involved in the regulation of the cell cycle and vascular endothelial growth factor. These target genes regulated by the biological clock genes are involved in DNA damage repair, cell proliferation and apoptosis.…”