ReviewThe role of circadian genes in the pathogenesis of colorectal cancer
Introduction
Colorectal cancer (CRC) is the third most frequently diagnosed malignancy worldwide and counts for about 10% cancer-related death in western countries. The majority of CRCs are not accompanied with hereditary or familial factors (Gao et al., 2017, Siegel et al., 2017). The developed countries’ life styles including frequent consumption of red meat, fat, alcohol, and smoking increase the risk of CRC initiation. In addition, bacterial infection (Eyvazi et al., 2020), heart disease, type 2 diabetes (T2DM), high blood pressure, and obesity are associated with increasing of CRC risk (Hadjipetrou et al., 2017, Obidike et al., 2019). CRC is a heterogeneous disease. The accumulation of several genetic and epigenetic changes in the colon epithelial cells is the main process which drives CRC initiation and progression (Okugawa et al., 2015, Ebrahimi et al., 2020). In adenoma-carcinoma cascade, the inactivation of adenomatous polyposis coli (APC) is the first event which changes the colon normal epithelium to adenoma. Following mutations in KRAS and TP53 genes, progression of adenoma to carcinoma occurs (Maffeis et al., 2019). CRCs are classified into subgroups based on the three principle pathophysiological pathways: chromosomal instability (CIN), microsatellite instability (MSI), and CpG island methylator phenotype (CIMP) (Nguyen and Duong, 2018, Jung et al., 2020).
CIN pathway is responsible for about 80–85% of CRC cases. In this pathway, neoplasia develops from adenomatous polyps due to inactivation of APC gene and finally transforms into adenocarcinomas via additional activating mutations in KRAS gene and inactivation of SMAD4 and Tp53 genes (Jung et al., 2020).
MSI happens due to changes in microsatellites following DNA mismatch repair deficiency in MMR genes like MLH1, MSH2, MSH6, and PMS2 (Lynch et al., 2008). CIMP subgroup is described based on CpG island hypermethylation at the promoters of some tumor suppressor genes. MLH1 promoter hyper methylation is common in this type of CRC (Toyota et al., 1999).
The CRC treatment plan composed of a combination of surgery, radiation therapy, chemotherapy and targeted therapy (Fig. 1). The response to surgery in cancers restricted to the wall of the colon is acceptable; however, the metastatic forms are not curable, and the palliative care is suggested to improve life quality and reduce the symptoms. Nowadays, targeted therapy of cancer is highly considered compared with conventional therapies due to its higher efficiency and lower side effects (Razi Soofiyani et al., 2017, RaziSoofiyani et al., 2017, Payandeh et al., 2019).
Circadian rhythms are the basic biological systems in most living creatures which are regulated by circadian clock placed in the suprachiasmatic nucleus in the hypothalamus. The circadian system controls various cellular procedures involved in tumor development like metabolism, DNA damage response, and cell cycle (Evans and Davidson, 2013, Shafi and Knudsen, 2019). Several investigations have demonstrated that interference in circadian rhythms lead to lots of health problems, including metabolic syndrome (Maroufi et al., 2016), cardiovascular dysfunction, immune dysregulation, reproductive problems, sleep disorders fatigue, learning difficulties, cancer progression, and carcinogenesis (Viswanathan et al., 2007, Froy, 2010, Khapre et al., 2010, Sellix and Menaker, 2011, Karantanos et al., 2014). The circadian principal clock pathway genes are circadian locomotor output cycles kaput protein (CLOCK), neuronal PAS domain protein 2 (NPAS2), ary1 hydrocarbon receptor nuclear translocator-like (ARNTL), period 1 (PER1), period 2 (PER2), period 3 (PER3), brain and muscle ARNT-like protein 1 (Bmal1), cryptochrome 1 (CRY1), cryptochrome 2 (CRY2), Timeless (TIM), and casein kinase 1-epsilon (CSNK1E).
During the past decades, the association of circadian genes with cancer development has been investigated extensively. For example, a study showed that melatonin, as a circadian rhythms regulator, is associated with cancer susceptibility (Gu et al., 2018). Disruption of circadian rhythm in knock-out mouse and human investigations has been known in a wide range of malignancies, including colorectal, lung, breast, ovarian, and hematologic malignancies in humans (Kettner et al., 2014). Furthermore, it has been shown that changes in CLOCK, PERs, CRYs, and TIMELESS gene expression are frequently associated with related gene methylation and cancer development and progression (Evans and Davidson, 2013). Previous studies indicated the associations of circadian gene expression and clinicopathological features and consequences in CRC. Identification of the details of the pathways in CRC helps researchers to explore new therapies for the malignancy. So, in this review, the association of various circadian genes in CRC development has been reviewed.
Section snippets
Circadian genes
Circadian genes are very important and vital group of genes which create an internal time-keeping system in different organisms and affect their behavior. While, exogenous signals like heat and light can affect those genes, most organisms organize their own behavior like mood, cognition, attention (Reppert and Weaver, 2001), metabolism (Green et al., 2008), physiology, such as circulating hormone levels (Lightman, 2016), and body temperature fluctuations into the 24 h solar cycle, using
The association of circadian genes dysregulation and various diseases such as cancer
The abnormal expression of circadian genes affects different diseases such as sleep disorders, metabolic processes, Alzheimer’s, cancer, etc. (Table 1).
The development of seasonal affective disorder (SAD) is created by replacing an amino acid (471 Leu/Ser) in neuronal PAS domain protein 2 (Npas2) (Johansson et al., 2003). A single nucleotide polymorphism (SNP) in the clock gene, in 3′ flanking region (3111 T to C), is associated with bipolar disease (Benedetti et al., 2003). Other kinds of SNP
Circadian genes and colorectal cancer
The clock genes control the expression of various genes such as cell-cycle regulators, oncogenes, and tumor suppressor genes in the time dependent manner. The clock-controlled genes regulate the timing of cellular basic functions like metabolism, DNA damage repair, and autophagy (Mazzoccoli et al., 2012). Also, the circadian system regulates the cell growth and death by affecting transcription/post-translational modification of critical proteins for DNA replication (Lee, 2006). Disrupted
Conclusion
The circadian system plays a significant role in gastrointestinal physiology, and changes in molecular circadian clock may be involved in colorectal cancer tumorgenesis. The circadian genes/proteins are frequently changed in colorectal malignancies and affect the phenotype of colon neoplastic cells, progression of cancer, survival of patients, and chemotherapy responses. To further understand the mechanisms regulated by the circadian genes and alternation in the genes involved in colorectal
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgement
The authors would like to thank the Clinical Research Development Unit of Sina Educational, Research, and Treatment Center, Tabriz University of Medical Sciences, Tabriz, Iran., for their assistance in this research.
Funding
This work was supported and funded scheme by Tabriz University of Medical Sciences. Grand number: IR.TBZMED.REC.1399.886.
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