Circadian Clock Genes Are Correlated with Prognosis and Immune Cell Infiltration in Colon Adenocarcinoma

Abstract

Background. Colon adenocarcinoma (COAD) is a malignancy with a high incidence and is associated with poor quality of life. Dysfunction of circadian clock genes and disruption of normal rhythms are associated with the occurrence and progression of many cancer types. However, studies that systematically describe the prognostic value and immune-related functions of circadian clock genes in COAD are lacking. Methods. Genomic data obtained from The Cancer Genome Atlas (TCGA) database was analyzed for expression level, mutation status, potential biological functions, and prognostic performance of core circadian clock genes in COAD. Their correlations with immune infiltration and TMB/MSI score were analyzed by Spearman’s correlation analysis. Pearson’s correlation analysis was performed to analyze their associations with drug sensitivity. Lasso Cox regression analysis was performed to construct a prognosis signature. Moreover, an mRNA-miRNA-lncRNA regulatory axis was also detected by ceRNA network. Results. In COAD tissues, the mRNA levels of CLOCK, CRY1, and NR1D1 were increased, while the mRNA levels of ARNTL, CRY2, PER1, PER3, and RORA were decreased. We also summarized the relative genetic mutation variation landscape. GO and KEGG pathway analyses demonstrated that these circadian clock genes were primarily correlated with the regulation of circadian rhythms and glucocorticoid receptor signaling pathways. COAD patients with high CRY2, NR1D1, and PER2 expression had worse prognosis. A prognostic model constructed based on the 9 core circadian clock genes predicted the COAD patients’ overall survival with medium to high accuracy. A significant association between prognostic circadian clock genes and immune cell infiltration was found. Moreover, the lncRNA KCNQ1OT1/hsa-miRNA-32-5p/PER2/CRY2 regulatory axis in COAD was also detected through a mRNA-miRNA-lncRNA network. Conclusion. Our results identified CRY2, NR1D1, and PER2 as potential prognostic biomarkers for COAD patients and correlated their expression with immune cell infiltration. The lncRNA KCNQ1OT1/hsa-miRNA-32-5p/PER2/CRY2 regulatory axis was detected in COAD and might play a vital role in the occurrence and progression of COAD.

Obesity, cancer risk, and time-restricted eating

“…In hematological malignancies, BMAL1 expression levels correlate inversely with MYC levels [ 76 ], the PER genes are downregulated in CLL [ 97 ], NPAS2 is up-regulated in AML patients [ 98 ], and the CRY genes show both up- and down-regulation in CLL and AML [ 99 , 100 ]. Similar associations have been reported in other cancers, including head and neck [ 101 ], colorectal cancer [ 83 , 102 ], liver cancer [ 103 ], and lung cancer [ 104 , 105 ] to name but a few. Overall, the accumulated data point to the importance of circadian rhythms in normal health and suggest that interventions to normalize disrupted rhythms in obesity and cancer could be beneficial.…”

Circadian clock as a possible control point in colorectal cancer progression (Review)

“…Per1-3 were reported to have tumour suppressor properties, but certain studies reached different conclusions (Table I). A total of seven studies determined that the expression of Per1 was significantly decreased in tumour tissue compared to healthy mucosa (37)(38)(39)(40)(41)(42)(43)(44). Furthermore, one study indicated a decrease in Per1 in undifferentiated tumours, while no differences were obtained in differentiated colon carcinomas (45), but two studies found no significant differences in Per1 between colon tumours and healthy mucosa (46,47).…”

“…Hasakova et al (50,53) found that Per2 was downregulated in tumour tissues of male patients with CRC, but Krugluger et al (45) determined that Per2 expression exhibited no differences in colon tumour tissues; the following six studies also confirmed this (38,(40)(41)(42)47). Another six studies examined the gene expression of Per3 and all found significant decreases (37)(38)(39)41,42,54). In addition, Alexander et al (55) found a Per3 gene length polymorphism, and the 5-repeat Per3 VNTR sequence may increase the chance of colorectal adenoma formation.…”

“…Further evidence has indicated that Cry2 suppresses colon tumour growth, but the role of Cry1 in cancer progression remains controversial. Compared to matched normal mucosa, gene expression of Cry1 was reported to be upregulated in colon carcinoma tissues by three studies (37,72,73), but two other studies claimed that the expression of Cry1 did not differ significantly between groups (39,46). Cry2 was identified to be downregulated in CRC tissues in three studies (37,39,50,72).…”

Dysregulation of Circadian Clock Genes Associated with Tumor Immunity and Prognosis in Patients with Colon Cancer

“…According to one study, CLOCK, CRY1, and NR1D1 mRNA expression was raised in COAD tissue. A bioinformatic study revealed that circadian rhythm genes were mostly 5 Computational and Mathematical Methods in Medicine associated with the glucocorticoid receptor pathway [15]. However, the functions of CCGs in the colorectal cancer remained largely to be unclear.…”