Rhythmic fluctuations have been identified in hepatic metabolic functions with a 24-h periodicity ( 22). The liver has a central and unique metabolic function in maintaining energy homeostasis via glycolysis and gluconeogenesis associated with fatty acid metabolism (biosynthesis/beta oxidation) ( 21). Prior studies have demonstrated the association between circadian rhythm alterations and the development of breast ( 15) and prostate cancer ( 16), B-cell lymphoma ( 17), non-small cell lung ( 18), testicular ( 19) and ovarian cancer ( 20). It is well-known that disturbances in the circadian rhythm may cause the development of diseases, including major depressive disorder, seasonal affective disorder, schizophrenia, bipolar disorder ( 4– 9), stress, desynchronosis ( 9), anxiety disorder, diabetes ( 10), obesity, diseases associated with aging ( 11), genome instability ( 12) and cancer ( 13, 14). The molecular clock of transcription involves a translational feedback mechanism of genes, including clock circadian regulator (CLOCK), period circadian clock (PER), aryl hydrocarbon receptor nuclear translocator like (BMAL1) and cryptochrome circadian clock (CRY), able to regulate a number of physiological properties, including body temperature, melatonin secretion, hormone secretion, blood pressure and the sleep-wake cycle ( 3). In humans, the circadian rhythms are controlled by a master pacemaker situated in the suprachiasmatic nuclei of the hypothalamus, which is synchronized to the photoperiod ( 1, 2). Finally, the results of the present study identified the microRNAs involved in the network formed by the overlapping of HepG2 and circadian genes.Ĭircadian rhythms control the 24 h cycle of specific metabolic functions required by living beings, ensuring an efficient metabolic homeostasis ( 1, 2). Furthermore, the genes that associate the circadian system with liver cancer were demonstrated to encode intrinsically disordered proteins. In addition, it was revealed that the CLOCK circadian regulator gene was associated, via cytoskeleton associated protein 5 (CKAP5), with the HUB genes of the HepG2 network, and that CKAP5 was associated with three other circadian genes (casein kinase 1ε, casein kinase 1δ and histone deacetylase 4) and 10 HepG2 genes (SH2 domain containing, ZW10 interacting kinetochore protein, aurora kinase B, cell division cycle 20, centromere protein A, inner centromere protein, mitotic arrest deficient 2 like 1, baculoviral IAP repeat containing 5, SPC24 NDC80 kinetochore complex component and kinesin family member 2C). The results of the present study demonstrated that 20/26 HUB genes were associated with the metabolic processes that control human circadian rhythms, which supports the hypothesis that a number of cancer types are dependent from circadian cycles. The present study aimed to identify whether these previously identified HUB genes participate in the network that controls the human circadian rhythms. In our previous study, a network analysis was performed on dysregulated genes in HepG2 cells, a hepatoblastoma cell line that lacks the viral infection, compared with normal hepatocytes, identifying the presence of 26 HUB genes. Network analysis is a useful approach in cancer biology as it provides information regarding the genes and proteins.
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