Gene Summary

Gene:PER3; period circadian clock 3
Aliases: GIG13
Summary:This gene is a member of the Period family of genes and is expressed in a circadian pattern in the suprachiasmatic nucleus, the primary circadian pacemaker in the mammalian brain. Genes in this family encode components of the circadian rhythms of locomotor activity, metabolism, and behavior. This gene is upregulated by CLOCK/ARNTL heterodimers but then represses this upregulation in a feedback loop using PER/CRY heterodimers to interact with CLOCK/ARNTL. Polymorphisms in this gene have been linked to sleep disorders. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2014]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:period circadian protein homolog 3
Source:NCBIAccessed: 25 June, 2015


What does this gene/protein do?
Show (6)
Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 25 June 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Hepatocellular Carcinoma
  • Risk Factors
  • Circadian Rhythm
  • Cancer Gene Expression Regulation
  • CLOCK Proteins
  • Period Circadian Proteins
  • Messenger RNA
  • Flavoproteins
  • Polymorphism
  • Tandem Repeat Sequences
  • Cryptochromes
  • Breast Cancer
  • Prostate Cancer
  • Chromosome 1
  • Cell Cycle Proteins
  • Adolescents
  • Liver Cancer
  • Promoter Regions
  • Gene Expression Profiling
  • Young Adult
  • Statistics, Nonparametric
  • Transcription Factors
  • Up-Regulation
  • China
  • Genetic Predisposition
  • Work Schedule Tolerance
  • Case-Control Studies
  • Nuclear Proteins
  • Colorectal Cancer
  • Single Nucleotide Polymorphism
  • Azacitidine
  • Genotype
  • Genetic Variation
  • Circadian Clocks
  • Tumor Markers
  • DNA Methylation
  • Down-Regulation
  • Immunohistochemistry
  • Gene Expression
Tag cloud generated 25 June, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: PER3 (cancer-related)

Geng P, Ou J, Li J, et al.
Genetic association between PER3 genetic polymorphisms and cancer susceptibility: a meta-analysis.
Medicine (Baltimore). 2015; 94(13):e568 [PubMed] Related Publications
The genes along the circadian pathways control and modulate circadian rhythms essential for the maintenance of physiological homeostasis through self-sustained transcription-translation feedback loops. PER3 (period 3) is a circadian pathway gene and its variants (rs1012477, 4/5-repeat) have frequently been associated with human cancer. The mixed findings, however, make the role of the 2 variants in cancer susceptibility elusive. We aimed in this article to clarify the association of PER3 variants with cancer. We collected genetic data from 8 studies, providing 6149 individuals for rs1012477 and 5241 individuals for 4/5-repeat. Based on the genotype and allele frequency, we chose the fixed-effects model to estimate risk of cancer. Overall analysis did not suggest a global role of rs1012477 in cancer susceptibility. For PER3 4/5-repeat variant, we found a moderate increase in risk of cancer among individuals with the 5-allele compared to individuals with the 4-allele, although this association was not statistically significant (homozygous model: odds ratio [OR] 1.17, 95% confidence interval [CI] 0.81-1.67; recessive model: OR 1.17, 95% CI 0.82-1.67). No substantial heterogeneity was revealed in this analysis. Our meta-analysis provides no evidence supporting a global association of PER3 genetic variants with the incidence of cancer.

Zhang Z, Ma F, Zhou F, et al.
Functional polymorphisms of circadian negative feedback regulation genes are associated with clinical outcome in hepatocellular carcinoma patients receiving radical resection.
Med Oncol. 2014; 31(12):179 [PubMed] Related Publications
Previous studies have demonstrated that circadian negative feedback loop genes play an important role in the development and progression of many cancers. However, the associations between single-nucleotide polymorphisms (SNPs) in these genes and the clinical outcomes of hepatocellular carcinoma (HCC) after surgical resection have not been studied so far. Thirteen functional SNPs in circadian genes were genotyped using the Sequenom iPLEX genotyping system in a cohort of 489 Chinese HCC patients who received radical resection. Multivariate Cox proportional hazards model and Kaplan-Meier curve were used for the prognosis analysis. Cumulative effect analysis and survival tree analysis were used for the multiple SNPs analysis. Four individual SNPs, including rs3027178 in PER1, rs228669 and rs2640908 in PER3 and rs3809236 in CRY1, were significantly associated with overall survival (OS) of HCC patients, and three SNPs, including rs3027178 in PER1, rs228729 in PER3 and rs3809236 in CRY1, were significantly associated with recurrence-free survival (RFS). Moreover, we observed a cumulative effect of significant SNPs on OS and RFS (P for trend < 0.001 for both). Survival tree analysis indicated that wild genotype of rs228729 in PER3 was the primary risk factor contributing to HCC patients' RFS. Our study suggests that the polymorphisms in circadian negative feedback loop genes may serve as independent prognostic biomarkers in predicting clinical outcomes for HCC patients who received radical resection. Further studies with different ethnicities are needed to validate our findings and generalize its clinical utility.

Hansen MV
Chronobiology, cognitive function and depressive symptoms in surgical patients.
Dan Med J. 2014; 61(9):B4914 [PubMed] Related Publications
Biological rhythms are essential for the regulation of many life processes. Disturbances of the circadian rhythm are known to affect human health, performance and well-being and the negative consequences are numerous and widespread. Cognitive dysfunction, fatigue, pain, sleep disturbances and mood disorders, such as anxiety and depression, are common problems arising around the time of surgery or in the course of a cancer diagnosis and subsequent treatment period. The importance of investigating prevention or treatment possibilities in these populations is significant due to the extent of the problems and the derived consequences on morbidity and mortality. Genetic predisposition to these problems is also an issue in focus. In this thesis we initially investigated whether the specific clock gene genotype PER(5/5) was associated with the development of postoperative cognitive dysfunction one week after non-cardiac surgery. We did not find any association, although this could have been due to the size of the study. Yet, if PER3(5/5) is associated with a higher incidence of postoperative cognitive dysfunction, the risk seems to be only modestly increased and by less than 10%. Melatonin is a hormone with well-known chronobiotic and hypnotic effects. In addition, exogenous melatonin is also known to have anxiolytic, analgesic, antidepressant and positive cognitive effects. Based on the lack of studies investigating these effects of melatonin, we conducted the MELODY trial in which we investigated the effect of 6 mg oral melatonin on depressive symptoms, anxiety, sleep, cognitive function and fatigue in patients with breast cancer in a three month time period after surgery. Melatonin had an effect on reducing the risk of developing depressive symptoms and also increased sleep efficiency perioperatively and total sleep time postoperatively. No effect was found on anxiety, sleep quality, sleepiness, general well-being or pain, however melatonin seemed to positively influence the ability to complete trial participation compared to placebo. Postoperative cognitive dysfunction was not a problem in this limited population. With regard to safety in our study, melatonin treatment for three months did not cause any serious adverse effects. Finally, we systematically reviewed the literature on the prophylactic or therapeutic effect of melatonin for depression or depressive symptoms in adult patients and assessed the safety of melatonin in these studies. The quantity, size and quality of trials investigating this question were not high and there was no clear evidence of an effect, although some studies were positive. In conclusion, further research is warranted with regard to the prophylactic effect and treatment effect of melatonin in depression, depressive symptoms, cognitive disturbances and symptom clusters of cancer patients in general. In addition, more hypothesis-generating studies with regard to the genetic heritability of POCD are needed.

Wirth MD, Burch JB, Hébert JR, et al.
Case-control study of breast cancer in India: Role of PERIOD3 clock gene length polymorphism and chronotype.
Cancer Invest. 2014; 32(7):321-9 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
BACKGROUND: This study examined a PERIOD3 (PER3) gene variable number tandem repeat polymorphism and chronotype as potential BrCA risk factors among Indian women.
METHODS: This case-control study included sporadic, histologically confirmed BrCA cases (n = 255) and controls (n = 249) from India with data collection from 2010-2012.
RESULTS: Women with the 4/5 or 5/5 PER3 genotype had a nonstatistically significant 33% increased odds of BrCA. Cases were more likely to have a morning (OR = 2.43, 95% CI = 1.23-4.81) or evening (OR = 2.55, 95% CI = 1.19-5.47) chronotype.
CONCLUSIONS: Findings are consistent with the possibility that extremes in chronotype may elicit circadian desynchronization, resulting in increased BrCA susceptibility.

Couto P, Miranda D, Vieira R, et al.
Association between CLOCK, PER3 and CCRN4L with non‑small cell lung cancer in Brazilian patients.
Mol Med Rep. 2014; 10(1):435-40 [PubMed] Related Publications
Circadian rhythms comprise of daily oscillations in a variety of biological processes and are regulated by an endogenous clock. Disruption of these rhythms has been associated with cancer progression, and understanding natural oscillations in cellular growth control, tumor suppression and cancer treatment, may reveal how clock and clock‑controlled genes are regulated in normal physiological functioning. To investigate the association between clock genes and non‑small cell lung cancer (NSCLC), we genotyped three tag SNPs (rs938836, rs17050680, rs3805213) in the Nocturnin gene (CCRN4L), five SNPs (rs228727, rs228644, rs228729, rs707467, rs104620202) in the period 3 (PER3) gene and one SNP (rs6855837) in the CLOCK gene, in 78 Brazilian patients with NSCLC. One tag SNP in CCRN4L (rs3805213) and another tag SNP from PER3 (rs228729) demonstrated a significant correlation with genotype and allele frequency in lung cancer (P=4.4x10‑3 and P=5.7x10‑2; P=0.004 and P=0.02, respectively). The results of our study suggest these polymorphisms in the CCRN4L and PER3 genes may represent a risk factor in the occurrence and development of NSCLC in Brazilian patients.

Hu ML, Yeh KT, Lin PM, et al.
Deregulated expression of circadian clock genes in gastric cancer.
BMC Gastroenterol. 2014; 14:67 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
BACKGROUND: Gastric cancer (GC), an aggressive malignant tumor of the alimentary tract, is a leading cause of cancer-related death. Circadian rhythm exhibits a 24-hour variation in physiological processes and behavior, such as hormone levels, metabolism, gene expression, sleep and wakefulness, and appetite. Disruption of circadian rhythm has been associated with various cancers, including chronic myeloid leukemia, head and neck squamous cell carcinoma, hepatocellular carcinoma, endometrial carcinoma, and breast cancer. However, the expression of circadian clock genes in GC remains unexplored.
METHODS: In this study, the expression profiles of eight circadian clock genes (PER1, PER2, PER3, CRY1, CRY2, CKIϵ, CLOCK, and BMAL1) of cancerous and noncancerous tissues from 29 GC patients were investigated using real-time quantitative reverse-transcriptase polymerase chain reaction and validated through immunohistochemical analysis.
RESULTS: We found that PER2 was significantly up-regulated in cancer tissues (p < 0.005). Up-regulated CRY1 expression was significantly correlated with more advanced stages (stage III and IV) (p < 0.05).
CONCLUSIONS: Our results suggest deregulated expressions of circadian clock genes exist in GC and circadian rhythm disturbance may be associated with the development of GC.

Karantanos T, Theodoropoulos G, Pektasides D, Gazouli M
Clock genes: their role in colorectal cancer.
World J Gastroenterol. 2014; 20(8):1986-92 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
Clock genes create a complicated molecular time-keeping system consisting of multiple positive and negative feedback loops at transcriptional and translational levels. This circadian system coordinates and regulates multiple cellular procedures implicated in cancer development such as metabolism, cell cycle and DNA damage response. Recent data support that molecules such as CLOCK1, BMAL1 and PER and CRY proteins have various effects on c-Myc/p21 and Wnt/β-catenin pathways and influence multiple steps of DNA damage response playing a critical role in the preservation of genomic integrity in normal and cancer cells. Notably, all these events have already been related to the development and progression of colorectal cancer (CRC). Recent data highlight critical correlations between clock genes' expression and pathogenesis, progression, aggressiveness and prognosis of CRC. Increased expression of positive regulators of this circadian system such as BMAL1 has been related to decrease overall survival while decreased expression of negative regulators such as PER2 and PER3 is connected with poorer differentiation, increased aggressiveness and worse prognosis. The implications of these molecules in DNA repair systems explain their involvement in the development of CRC but at the same time provide us with novel targets for modern therapeutic approaches for patients with advanced CRC.

Hong Z, Feng Z, Sai Z, Tao S
PER3, a novel target of miR-103, plays a suppressive role in colorectal cancer in vitro.
BMB Rep. 2014; 47(9):500-5 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
Colorectal cancer has become the third most common cancer and leads to high mortality worldwide. Although colorectal cancer has been studied widely, the underlying molecular mechanism remains unclear. PER3 is related to tumor differentiation and the progression of colorectal cancer. High expression of miR-103 is associated with poor prognosis in patients with colorectal cancer. However, the relationship between miR-103 and PER3 in CRC cells remains unclear. In this study, we found that PER3 was downregulated in CRC tissues and CRC cell lines, whereas miR-103 was upregulated in CRC cell lines. We also found that PER3 promoted CRC cells apoptosis. These results indicate that PER3 plays a suppressive role in CRC cells. Moreover, we found that PER3 was targeted, at least partially, by miR-103. Taken together, we provide evidence to characterize the role of PER3 in CRC, which may be a new therapeutic target for CRC.

Madden MH, Anic GM, Thompson RC, et al.
Circadian pathway genes in relation to glioma risk and outcome.
Cancer Causes Control. 2014; 25(1):25-32 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
PURPOSE: There is growing evidence that circadian disruption may alter risk and aggressiveness of cancer. We evaluated common genetic variants in the circadian gene pathway for associations with glioma risk and patient outcome in a US clinic-based case-control study.
METHODS: Subjects were genotyped for 17 candidate single nucleotide polymorphisms in ARNTL, CRY1, CRY2, CSNK1E, KLHL30, NPAS2, PER1, PER3, CLOCK, and MYRIP. Unconditional logistic regression was used to estimate age and gender-adjusted odds ratios (OR) and 95 % confidence intervals (CI) for glioma risk under three inheritance models (additive, dominant, and recessive). Proportional hazards regression was used to estimate hazard ratios for glioma-related death among 441 patients with high-grade tumors. Survival associations were validated using The Cancer Genome Atlas (TCGA) dataset.
RESULTS: A variant in PER1 (rs2289591) was significantly associated with overall glioma risk (per variant allele OR 0.80; 95 % CI 0.66-0.97; p trend = 0.027). The variant allele for CLOCK rs11133391 under a recessive model increased risk of oligodendroglioma (OR 2.41; 95 % CI 1.31-4.42; p = 0.005), though not other glioma subtypes (p for heterogeneity = 0.0033). The association remained significant after false discovery rate adjustment (p = 0.008). Differential associations by gender were observed for MYRIP rs6599077 and CSNK1E rs1534891 though differences were not significant after adjustment for multiple testing. No consistent mortality associations were identified. Several of the examined genes exhibited differential expression in glioblastoma multiforme versus normal brain in TCGA data (MYRIP, ARNTL, CRY1, KLHL30, PER1, CLOCK, and PER3), and expression of NPAS2 was significantly associated with a poor patient outcome in TCGA patients.
CONCLUSION: This exploratory analysis provides some evidence supporting a role for circadian genes in the onset of glioma and possibly the outcome of glioma.

Karantanos T, Theodoropoulos G, Gazouli M, et al.
Association of the clock genes polymorphisms with colorectal cancer susceptibility.
J Surg Oncol. 2013; 108(8):563-7 [PubMed] Related Publications
BACKGROUND AND OBJECTIVES: The circadian rhythm regulates the cell cycle progression and DNA damage response. The aim of our study was to investigate the association between polymorphisms in the CLOCK1, PER2, and PER3 genes with the colorectal cancer (CRC) susceptibility and clinicopathological variables.
METHODS: Four hundred two CRC patients and 480 healthy controls were included in a case-control study. Genotype and allelic frequencies of 311T>C (rs1801260) in CLOCK1 gene, G3853A (rs934945) in PER2 gene and 4/5 repeats polymorphisms in PER3 gene were evaluated by the polymerase chain reaction (PCR) restriction fragment length polymorphism method in the DNA extracted from the peripheral blood of patients and controls.
RESULTS: The frequencies of the 311T>C CLOCK1 gene, CC genotype and C allele were significantly higher among CRC patients compared to controls (P < 0.0001) elevating the CRC risk by 2.78- and 1.78-fold respectively. No correlation was found between G3853A and 4/5 repeats polymorphisms and CRC risk. The C/G/5 and C/G/4 repeats haplotypes were higher in CRC patients (P = 0.0009 and P = 0.038) elevating the CRC risk by 60% and 89% respectively. No correlation was found between any polymorphism and clinicopathological characteristics of CRC patients.
CONCLUSION: The 311T>C polymorphism in the CLOCK1 gene significantly increases the risk for CRC development while it does not affect the outcome of CRC patients.

Zienolddiny S, Haugen A, Lie JA, et al.
Analysis of polymorphisms in the circadian-related genes and breast cancer risk in Norwegian nurses working night shifts.
Breast Cancer Res. 2013; 15(4):R53 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
INTRODUCTION: Some studies have suggested that night work may be associated with an increased risk of breast cancer in nurses. We aimed to explore the role of circadian gene polymorphisms in the susceptibility to night work-related breast cancer risk.
METHODS: We conducted a nested case-control study of Norwegian nurses comprising 563 breast cancer cases and 619 controls within a cohort of 49,402 Norwegian nurses ages 35 to 74 years. We studied 60 single-nucleotide polymorphisms (SNPs) in 17 genes involved in the regulation of the circadian rhythm in cases and controls. The data were analyzed in relation to the two exposure variables "maximum number of consecutive night shifts ever worked" and "maximum number of consecutive night shifts worked for at least 5 years." The odds of breast cancer associated with each SNP was calculated in the main effects analysis and in relation to night shift work. The statistically significant odds ratios were tested for noteworthiness using two Bayesian tests: false positive report probability (FPRP) and Bayesian false discovery probability (BFDP).
RESULTS: In the main effects analysis, CC carriers of rs4238989 and GG carriers of rs3760138 in the AANAT gene had increased risk of breast cancer, whereas TT carriers of BMAL1 rs2278749 and TT carriers of CLOCK rs3749474 had reduced risk. The associations were found to be noteworthy using both the FPRP and BFDP tests. With regard to the effect of polymorphisms and night work, several significant associations were observed. After applying FPRP and BFDP in women with at least four night shifts, an increased risk of breast cancer was associated with variant alleles of SNPs in the genes AANAT (rs3760138, rs4238989), BMAL1 (rs2290035, rs2278749, rs969485) and ROR-b (rs3750420). In women with three consecutive night shifts, a reduced risk of breast cancer was associated with carriage of variant alleles of SNPs in CLOCK (rs3749474), BMAL1 (rs2278749), BMAL2 (rs2306074), CSNK1E (rs5757037), NPAS2 (rs17024926), ROR-b (rs3903529, rs3750420), MTNR1A (rs131113549) and PER3 (rs1012477).
CONCLUSIONS: Significant and noteworthy associations between several polymorphisms in circadian genes, night work and breast cancer risk were found among nurses who had worked at least three consecutive night shifts.

Relles D, Sendecki J, Chipitsyna G, et al.
Circadian gene expression and clinicopathologic correlates in pancreatic cancer.
J Gastrointest Surg. 2013; 17(3):443-50 [PubMed] Related Publications
INTRODUCTION: The circadian rhythm is responsible for physiologic homeostasis, behavior, and components of multiple metabolic processes. Disruption of the circadian rhythm is associated with cancer development, and several circadian clock genes have been implicated in loss of cell cycle control, impaired DNA damage repair, and subsequent tumor formation. Here, we investigated the expression profiles of several circadian clock genes in pancreatic ductal adenocarcinoma (PDA).
METHODS: Quantitative real-time polymerase chain reaction was used to examine the circadian clock genes (brain-muscle-like (Bmal)-ARNTL, circadian locomotor output cycles kaput (Clock), cryptochrome 1 (Cry1), cryptochrome 2 (Cry2), casein kinase 1ε (CK1ε), period 1 (Per1), period 2 (Per2), period 3 (Per3), timeless (Tim), and timeless-interacting protein (Tipin)) in PDA, as well as matching adjacent and benign tissue. Logistic regression models with robust variance were used to analyze the gene expression levels, and Kaplan-Meier survival curves were generated based on gene expression.
RESULTS: In the tumor tissue of PDA patients, compared to their matched adjacent tissue, expression levels of all circadian genes were lower, with statistical significance for Per1, Per2, Per3, Cry1, Cry2, Tipin, Tim, CK1ε, Bmal-ARNTL, and Clock (p < 0.025). PDA tumors also expressed significantly lower levels of the circadian genes when compared to benign lesions for Per1, Per2, Per3, Cry2, Tipin, and CK1ε. A significant association between low levels of expression in the tumors and reduced survival was found with Per1, Per2, Per3, Cry2, Tipin, CK1ε, Clock, and Bmal-ARNTL.
CONCLUSIONS: Our results reveal for the first time a dysregulated transcription of several circadian genes in PDA. Elevation of the gene levels in the benign and matched adjacent tissues may be indicative of their role during the process of tumorigenesis. The potential of using circadian genes as predictive markers of the outcomes and survival and distinguishing PDA from benign pancreas must be studied in larger populations to validate and demonstrate their eventual clinical utility.

Zhao B, Lu J, Yin J, et al.
A functional polymorphism in PER3 gene is associated with prognosis in hepatocellular carcinoma.
Liver Int. 2012; 32(9):1451-9 [PubMed] Related Publications
BACKGROUND: Previous studies have revealed that circadian genes play important roles in cell proliferation, apoptosis, cell cycle control, DNA damage response and treatment response of chemotherapy agents in cancers.
AIMS: We hypothesized that the polymorphisms in circadian genes may be associated with prognosis of hepatocellular carcinoma (HCC) patients treated with transcatheter arterial chemoembolization (TACE).
METHODS: Twelve functional single nucleotide polymorphisms (SNPs) in circadian negative feedback regulation genes (including CRY1, CRY2, PER1, PER2 and PER3) were genotyped using Sequenom iPLEX genotyping method in 337 HCC patients treated with TACE and analysed for associations with overall survival.
RESULTS: Our data showed that one SNP rs2640908 in PER3 gene was significantly associated with overall survival of HCC patients (P = 0.027). Patients carrying at least one variant allele of rs2640908 (WV + VV) had a significantly decreased risk of death (hazard ratio, 0.71; 95% confidence interval, 0.53-0.90), when compared with those carrying homozygous wild-type alleles (WW). Kaplan-Meier analyses showed a significantly longer median survival time in patients with WV + VV genotypes of SNP rs2640908 than those with WW genotype (11.6 months vs. 8.1 months; log rank P = 0.030). In addition, we also observed a significant difference on the genotype distribution of SNP rs2640908 in patients with and without portal vein thrombus (P = 0.041).
CONCLUSIONS: Our study provides the first evidence that a single functional polymorphism of PER3 gene is significantly associated with overall survival in HCC patients treated with TACE.

Neumann O, Kesselmeier M, Geffers R, et al.
Methylome analysis and integrative profiling of human HCCs identify novel protumorigenic factors.
Hepatology. 2012; 56(5):1817-27 [PubMed] Related Publications
UNLABELLED: To identify new tumor-suppressor gene candidates relevant for human hepatocarcinogenesis, we performed genome-wide methylation profiling and vertical integration with array-based comparative genomic hybridization (aCGH), as well as expression data from a cohort of well-characterized human hepatocellular carcinomas (HCCs). Bisulfite-converted DNAs from 63 HCCs and 10 healthy control livers were analyzed for the methylation status of more than 14,000 genes. After defining the differentially methylated genes in HCCs, we integrated their DNA copy-number alterations as determined by aCGH data and correlated them with gene expression to identify genes potentially silenced by promoter hypermethylation. Aberrant methylation of candidates was further confirmed by pyrosequencing, and methylation dependency of silencing was determined by 5-aza-2'-deoxycytidine (5-aza-dC) treatment. Methylation profiling revealed 2,226 CpG sites that showed methylation differences between healthy control livers and HCCs. Of these, 537 CpG sites were hypermethylated in the tumor DNA, whereas 1,689 sites showed promoter hypomethylation. The hypermethylated set was enriched for genes known to be inactivated by the polycomb repressive complex 2, whereas the group of hypomethylated genes was enriched for imprinted genes. We identified three genes matching all of our selection criteria for a tumor-suppressor gene (period homolog 3 [PER3], insulin-like growth-factor-binding protein, acid labile subunit [IGFALS], and protein Z). PER3 was down-regulated in human HCCs, compared to peritumorous and healthy liver tissues. 5-aza-dC treatment restored PER3 expression in HCC cell lines, indicating that promoter hypermethylation was indeed responsible for gene silencing. Additionally, functional analysis supported a tumor-suppressive function for PER3 and IGFALS in vitro.
CONCLUSION: The present study illustrates that vertical integration of methylation data with high-resolution genomic and transcriptomic data facilitates the identification of new tumor-suppressor gene candidates in human HCC.

Mazzoccoli G, Piepoli A, Carella M, et al.
Altered expression of the clock gene machinery in kidney cancer patients.
Biomed Pharmacother. 2012; 66(3):175-9 [PubMed] Related Publications
BACKGROUND AND AIM: Kidney cancer is associated with alteration in the pathways regulated by von Hippel-Lindau protein and hypoxia inducible factor α. Tight interrelationships have been evidenced between hypoxia response pathways and circadian pathways. The dysregulation of the circadian clock circuitry is involved in carcinogenesis. The aim of our study was to evaluate the clock gene machinery in kidney cancer.
METHODS: mRNA expression levels of the clock genes ARNTL1, ARNTL2, CLOCK, PER1, PER2, PER3, CRY1, CRY2, TIMELESS, TIPIN and CSNK1E and of the clock controlled gene SERPINE1 were evaluated by DNA microarray assays and by qRT-PCR in primary tumor and matched nontumorous tissue collected from a cohort of 11 consecutive kidney cancer patients.
RESULTS: In kidney tumor tissue, we found down-regulation of PER2 (median=0.658, Q1-Q3=0.562-0.744, P<0.01), TIMELESS (median=0.705, Q1-Q3=0.299-1.330, P=0.04) and TIPIN (median=0.556, Q1-Q3=0.385-1.945, P=0.01), up-regulation of SERPINE1 (median=1.628, Q1-Q3=0.339-4.071, P=0.04), whereas the expression of ARNTL2 (median=0.605, Q1-Q3=0.318-1.738, P=0.74) and CSNK1E (median=0.927, Q1-Q3=0.612-2.321, P=0.33) did not differ. A statistically significant correlation was evidenced between mRNA levels of PER2 and CSNKIE (r=0.791, P<0.01), PER2 and TIPIN (r=0.729, P=0.01), PER2 and SERPINE1 (r=0.704, P=0.01), TIMELESS and TIPIN (r=0.605, P=0.04), TIMELESS and CSNKIE (r=0.637, P=0.03), TIPIN and CSNKIE (r=0.940, P<0.01).
CONCLUSION: In kidney cancer, the circadian clock circuitry is deregulated and the altered expression of the clock genes might be involved in disease onset and progression.

Wang X, Yan D, Teng M, et al.
Reduced expression of PER3 is associated with incidence and development of colon cancer.
Ann Surg Oncol. 2012; 19(9):3081-8 [PubMed] Related Publications
BACKGROUND: Period 3 (PER3), a circadian regulation protein, influences cell cycle, growth, and differentiation. The aim of the present study was to determine whether PER3 expression is associated with colon cancer incidence and progression.
METHODS: PER3 expression was analyzed in the normal and cancerous tissues from patients with colon cancer by establishing a long serial analysis of gene expression (SAGE) database as well as by real-time PCR and immunohistochemistry.
RESULTS: As compared with normal tissue, a 2.8-fold decrease in PER3 mRNA levels in colon cancerous tissue was observed. Real-time PCR analysis revealed that PER3 mRNA levels in tumor tissues were lower than in normal tissues (P < 0.001) in both patients with colon tumor and those with rectal tumor. In addition, PER3 expression was related to multiple clinicopathologic factors, including tumor location, differentiation, and stage. Furthermore, the incidence of death was higher in subjects with PER3-negative tumors (P = 0.025); the estimated overall survival time was 71.5 ± 2.2 months and 58.6 ± 5.0 months in subjects with PER3-positive and PER3-negative tumors, respectively (P = 0.020).
CONCLUSIONS: PER3 may play a role in colon cancer progression.

Pazienza V, Piepoli A, Panza A, et al.
SIRT1 and the clock gene machinery in colorectal cancer.
Cancer Invest. 2012; 30(2):98-105 [PubMed] Related Publications
SIRT1 and the clock genes are involved in carcinogenesis. We evaluated SIRT1 expression in 19 human colorectal cancer (CRC) specimens and clock gene expression in SIRT1-overexpressing CaCo2 and SW480 cells. In CRC, SIRT1 mean expression level was decreased. Compared to CaCo2 cells, SW480 cells displayed lower levels of SIRT1 and PER3 and higher levels of ARNTL1, CLOCK, PER1, PER2, CRY1, TIPIN, and CSNKIE. SIRT1 overexpression induced PER1 upregulation in CaCo2 and downregulation in SW480 cells. SIRT1 expression was heterogeneous in human CRC and in CRC cell lines. These results might have relevant implications for a better understanding of colorectal carcinogenesis.

Hsu CM, Lin SF, Lu CT, et al.
Altered expression of circadian clock genes in head and neck squamous cell carcinoma.
Tumour Biol. 2012; 33(1):149-55 [PubMed] Related Publications
Head and neck squamous cell carcinoma (HNSCC) means a group of cancers developed from the upper aerodigestive tract, and 90% of them are squamous cell carcinomas. HNSCC is the tenth most commonly diagnosed form of cancer in males worldwide, but it is the seventh most common cause of cancer-related death. The circadian clock regulates daily rhythmic variations in various physiologic processes including sleep and activity, appetite, hormone levels, metabolism, and gene expression. Many recent studies have demonstrated that the disruption of circadian rhythm is associated with cancer development and tumor progression, such as chronic myeloid leukemia, hepatocellular carcinoma, endometrial carcinoma, and breast cancer. However the direct links between aberrant circadian clock gene expression and human malignancies, including HNSCC, remain largely unknown. In this study, the expression profiles of nine circadian clock genes of cancer tissue and noncancerous part from 40 patients of HNSCC were investigated. The expression of PER1, PER2, PER3, CRY1, CRY2, CKIε, and BMAL1 showed significant downregulation in the cancer tissues (p < 0.005). Downregulated PER3, CRY2, and BMAL1 expression was correlated with more advanced cancer stages (p < 0.05). Downregulated PER3 and upregulated TIM expression correlated with larger tumor size (p < 0.05), and lower expression of PER3 correlated with deeper tumor invasion (p < 0.05). Poor survival was related to lower expression of PER1 (p < 0.05) and PER3 (p < 0.01). These results indicate a possible association of circadian clock gene, especially PER3, expression with the pathogenesis of HNSCC.

Mazzoccoli G, Panza A, Valvano MR, et al.
Clock gene expression levels and relationship with clinical and pathological features in colorectal cancer patients.
Chronobiol Int. 2011; 28(10):841-51 [PubMed] Related Publications
The clock gene machinery controls cellular metabolism, proliferation, and key functions, such as DNA damage recognition and repair. Dysfunction of the circadian clock is involved in tumorigenesis, and altered expression of some clock genes has been found in cancer patients. The aim of this study was to evaluate the expression levels of core clock genes in colorectal cancer (CRC). Quantitative real-time polymerase chain reaction (qPCR) was used to examine ARNTL1, CLOCK, PER1, PER2, PER3, CRY1, CRY2, Timeless (TIM), TIPIN, and CSNK1? expression levels in the tumor tissue and matched apparently healthy mucosa of CRC patients. In the tumor tissue of CRC patients, compared to their matched healthy mucosa, expression levels of ARNTL1 (p=.002), PER1 (p=.002), PER2 (p=.011), PER3 (p=.003), and CRY2 (p=.012) were lower, whereas the expression level of TIM (p=.044) was higher. No significant difference was observed in the expression levels of CLOCK (p=.778), CRY1 (p=.600), CSNK1 (p=.903), and TIPIN (p=.136). As to the clinical and pathological features, a significant association was found between low CRY1 expression levels in tumor mucosa and age (p=.026), and female sex (p=.005), whereas high CRY1 expression levels in tumor mucosa were associated with cancer location in the distal colon (p?=?.015). Moreover, high TIM mRNA levels in the tumor mucosa were prevalent whenever proximal lymph nodes were involved (p= .013) and associated with TNM stages III-IV (p=.005) and microsatellite instability (p=.015). Significantly poorer survival rates were evidenced for CRC patients with lower expression in the tumor tissue of PER1 (p=.010), PER3 (p= .010), and CSNKIE (p=.024). In conclusion, abnormal expression levels of core clock genes in CRC tissue may be related to the process of tumorigenesis and exert an influence on host/tumor interactions.

Sato F, Wu Y, Bhawal UK, et al.
PERIOD1 (PER1) has anti-apoptotic effects, and PER3 has pro-apoptotic effects during cisplatin (CDDP) treatment in human gingival cancer CA9-22 cells.
Eur J Cancer. 2011; 47(11):1747-58 [PubMed] Related Publications
PERIOD (PER) proteins are transcriptional regulators that are involved in circadian rhythms, sleep homeostasis, cell proliferation and tumour progression. We previously showed that the expression of PER1 was related to the regulation of apoptosis in human pancreatic cancer and hepatocellular carcinoma cells. However, the significance of PER in oral cancer has not been reported, and the detailed molecular mechanisms by which anti-tumour drug induces apoptosis in gingival cancer cells are not well understood. We examined whether PER1 and PER3 are involved in the regulation of apoptosis in human gingival cancer CA9-22 cells. The expression of PER1 and PER3 was upregulated and downregulated, respectively, by cis-diamminedichloroplatinum (II) (cisplatin: CDDP) treatment in CA9-22 cells, whereas CDDP treatment had little effects on the expression of PER1 and PER3 in human gingival fibroblasts (HGF-1). We found that short interference RNA (siRNA)-mediated knockdown of PER1 enhanced apoptosis of CA9-22 cells, and that PER1 regulated the amount of Bim, an apoptosis-related molecule. On the other hand, PER3 knockdown had an inhibitory effect on the apoptosis of CA9-22 cells induced by CDDP treatment. These results suggest that the alternation of expression of PER1 and PER3 was related to the apoptosis of CA9-22 cells. Furthermore, PER1 was intensely stained in the gingival cancer tissues, whereas PER3 was significantly stained in the non-tumour tissues by immunohistochemistry. These findings suggest that PER1 and PER3 have anti-apoptotic and pro-apoptotic effects in human gingival cancer CA9-22 cells, respectively. The balance of PER1 and PER3 may modulate apoptotic reactions in gingival cancer cells.

Yang MY, Yang WC, Lin PM, et al.
Altered expression of circadian clock genes in human chronic myeloid leukemia.
J Biol Rhythms. 2011; 26(2):136-48 [PubMed] Related Publications
Circadian clock genes use transcriptional-translational feedback loops to control circadian rhythms. Recent studies have demonstrated that expression of some circadian clock genes displays daily oscillation in peripheral tissues including peripheral blood and bone marrow. Circadian rhythms regulate various functions of human body, and the disruption of circadian rhythm has been associated with cancer development and tumor progression. However, the direct links between aberrant circadian clock gene expression and human disorders remain largely unknown. In this study, comparisons were made between the expression profiles of 9 circadian clock genes from peripheral blood mononuclear cells (PBMCs) and polymorphonuclear cells (PMNs) from 18 healthy volunteers. Peripheral blood (PB) total leukocytes from 54 healthy volunteers and 95 patients with chronic myeloid leukemia (CML) were also investigated. Similar expression profiles of all 9 circadian clock genes were observed in PBMCs and PMNs of healthy individuals. In PB total leukocytes of healthy individuals, the daily pattern of PER1, PER2, PER3, CRY1, CRY2, and CKIε expression level peaked at 0800 h, and BMAL1 peaked at 2000 h. Daily pattern expression of these 7 genes was disrupted in newly diagnosed pre-imatinib mesylate-treated and blast crisis-phase patients with CML. Partial daily pattern gene expression recoveries were observed in patients with CML with complete cytogenetic response and major molecular response. The expression of CLOCK and TIM did not show a time-dependent variation among the healthy and patients with CML. These results indicate a possible association of the disrupted daily patterns of circadian clock gene expression with the pathogenesis of CML.

Oshima T, Takenoshita S, Akaike M, et al.
Expression of circadian genes correlates with liver metastasis and outcomes in colorectal cancer.
Oncol Rep. 2011; 25(5):1439-46 [PubMed] Related Publications
Circadian rhythms are daily oscillations in various biological processes, generated by the feedback loops of eight core circadian genes: Period1 (Per1), Period2 (Per2), Period3 (Per3), Cryptochrome1 (Cry1), Cryptochrome2 (Cry2), Clock, Bmal1 and Casein Kinase I ε (CKIε). Recent studies have suggested that circadian genes participate in the growth and development of various cancers. This study examined the relations of circadian gene expression to clinicopathological factors and outcomes in patients with colorectal cancer. We studied surgical specimens of cancer tissue and adjacent normal mucosa obtained from 202 patients with untreated colorectal cancer. The relative expression levels of the circadian genes in the specimens were measured by quantitative real-time, reverse-transcription polymerase chain reaction. Expression of the Clock gene and the CKIε gene in cancer tissue were significantly higher compared to that in adjacent normal mucosa. Expression of the Per1 and Per3 genes in cancer tissue was significantly lower compared to that in adjacent normal mucosa. Analysis of the relations between clinicopathological features and expression of the eight circadian genes in cancer tissue showed that high expression of the Bmal1 gene and low expression of the Per1 gene correlated with liver metastasis. On analysis of the relations between outcomes and gene expression, high expression of the Per2 gene was associated with significantly better outcomes than low expression of the Per2 gene. Overexpression of the Bmal1 gene and reduced expression of the Per1 gene may thus be useful predictors of liver metastasis. Moreover, reduced expression of the Per2 gene may be a predictor of outcomes in patients with colorectal cancer.

Climent J, Perez-Losada J, Quigley DA, et al.
Deletion of the PER3 gene on chromosome 1p36 in recurrent ER-positive breast cancer.
J Clin Oncol. 2010; 28(23):3770-8 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
PURPOSE: To investigate the role of the PER3 circadian rhythm gene, located within the commonly deleted region of chromosome 1p36, in human breast cancer development.
PATIENTS AND METHODS: The frequency of genetic alterations at 1p36 and PER3 gene copy number status were analyzed in 180 lymph node-negative breast cancers from patients who had received treatment with chemotherapy and/or tamoxifen. The expression levels of PER3 were also analyzed using published microarray profiles from > 400 breast cancer samples. Finally, the effect of loss of Per3 on tumor susceptibility was tested using two mouse models of breast cancer.
RESULTS: Deletion of PER3 is directly related to tumor recurrence in patients with estrogen receptor (ER) - positive breast cancers treated with tamoxifen. Low expression of PER3 mRNA is associated with poor prognosis, particularly in a subset of tumors that are ER positive, and either luminal A or ERBB2-positive tumors. Mice deficient in Per3 showed increased susceptibility to breast cancer induced by carcinogen treatment or by overexpression of Erbb2.
CONCLUSION: Disruption of PER3 function may serve as an indicator of probability of tumor recurrence in patients with ER-positive tumors. Further investigations of this pathway may reveal links between deregulation of sleep homeostasis and breast tumorigenesis.

Stevens RG
Working against our endogenous circadian clock: Breast cancer and electric lighting in the modern world.
Mutat Res. 2009 Nov-Dec; 680(1-2):106-8 [PubMed] Related Publications
Breast cancer incidence increases rapidly as societies industrialize. Many changes occur during the industrialization process, one of which is a dramatic alteration in the lighted environment from a sun-based system to an electricity-based system. Increasingly, the natural dark period at night is being seriously eroded for the bulk of humanity. Based on the fact that light during the night can suppress melatonin, and also disrupt the circadian rhythm, it was proposed in 1987 that increasing use of electricity to light the night accounts in part for the rising risk of breast cancer globally. Predictions from the theory include: non-day shift work increases risk, blindness lowers risk, long sleep duration lowers risk, and population level community nighttime light level co-distributes with breast cancer incidence. Thus far, studies of these predictions are consistent in support of the theory. A new avenue of research has been on function of circadian genes and whether these are related to breast cancer risk. In particular, a length variant of Per3 (5-VNTR) has been associated with increased risk in young women, and this same 5-VNTR variant has also been found to predict morning diurnal type and shorter sleep duration compared to the 4-VNTR variant. An important question is how an effect of light-at-night (LAN) exposure on breast cancer risk might be modified by polymorphisms and/or epigenetic alterations in the circadian genes, and conversely whether light-at-night exposure (e.g., shift work) can induce deleterious epigenetic changes in these genes.

Zhu Y, Stevens RG, Hoffman AE, et al.
Testing the circadian gene hypothesis in prostate cancer: a population-based case-control study.
Cancer Res. 2009; 69(24):9315-22 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
Circadian genes are responsible for maintaining the ancient adaptation of a 24-hour circadian rhythm and influence a variety of cancer-related biological pathways, including the regulation of sex hormone levels. However, few studies have been undertaken to investigate the role of circadian genes in the development of prostate cancer, the most common cancer type among men (excluding nonmelanoma skin cancer). The current genetic association study tested the circadian gene hypothesis in relation to prostate cancer by genotyping a total of 41 tagging and amino acid-altering single nucleotide polymorphisms (SNP) in 10 circadian-related genes in a population-based case-control study of Caucasian men (n = 1,308 cases and 1,266 controls). Our results showed that at least one SNP in nine core circadian genes (rs885747 and rs2289591 in PER1; rs7602358 in PER2; rs1012477 in PER3; rs1534891 in CSNK1E; rs12315175 in CRY1; rs2292912 in CRY2; rs7950226 in ARNTL; rs11133373 in CLOCK; and rs1369481, rs895521, and rs17024926 in NPAS2) was significantly associated with susceptibility to prostate cancer (either overall risk or risk of aggressive disease), and the risk estimate for four SNPs in three genes (rs885747 and rs2289591 in PER1, rs1012477 in PER3, and rs11133373 in CLOCK) varied by disease aggressiveness. Further analyses of haplotypes were consistent with these genotyping results. Findings from this candidate gene association study support the hypothesis of a link between genetic variants in circadian genes and prostate cancer risk, warranting further confirmation and mechanistic investigation of circadian biomarkers in prostate tumorigenesis.

Chu LW, Zhu Y, Yu K, et al.
Correlation between circadian gene variants and serum levels of sex steroids and insulin-like growth factor-I.
Cancer Epidemiol Biomarkers Prev. 2008; 17(11):3268-73 [PubMed] Related Publications
A variety of biological processes, including steroid hormone secretion, have circadian rhythms, which are influenced by nine known circadian genes. Previously, we reported that certain variants in circadian genes were associated with risk for prostate cancer. To provide some biological insight into these findings, we examined the relationship of five variants of circadian genes, including NPAS2 (rs2305160:G > A), PER1 (rs2585405:G > C), CSNK1E (rs1005473:A > C), PER3 (54-bp repeat length variant), and CRY2 (rs1401417:G > C), with serum levels of sex steroids and insulin-like growth factor (IGF)-I and IGF-binding protein 3 (IGFBP3) in 241 healthy elderly Chinese men (mean age of 71.5). Age-adjusted and waist-to-hip ratio-adjusted ANOVA followed by likelihood ratio tests (LRT) showed that the NPAS2 variant A allele was associated with lower free and bioavailable testosterone (P(LRT) = 0.02 and 0.01, respectively) compared with the GG genotype. In addition, the PER1 variant was associated with higher serum levels of sex hormone-binding globulin levels (Ptrend = 0.03), decreasing 5alpha-androstane-3alpha, 17beta-diol glucuronide levels (Ptrend = 0.02), and decreasing IGFBP3 levels (Ptrend = 0.05). Furthermore, the CSNK1E variant C allele was associated with higher testosterone to dihydrotestosterone ratios (P(LRT) = 0.01) compared with the AA genotype, whereas the longer PER3 repeat was associated with higher serum levels of IGF-I (P(LRT) = 0.03) and IGF-I to IGFBP3 ratios (P(LRT) = 0.04). The CRY2 polymorphism was not associated with any biomarkers analyzed. Our findings, although in need of confirmation, suggest that variations in circadian genes are associated with serum hormone levels, providing biological support for the role of circadian genes in hormone-related cancers.

Tokunaga H, Takebayashi Y, Utsunomiya H, et al.
Clinicopathological significance of circadian rhythm-related gene expression levels in patients with epithelial ovarian cancer.
Acta Obstet Gynecol Scand. 2008; 87(10):1060-70 [PubMed] Related Publications
OBJECTIVE: Recent studies implicate circadian genes in the regulation of cell cycle, apoptosis, and cell proliferation at a molecular level. These genesey affect cancer incidence, prognosis, and chemosensitivity. In this study, we measured the expression levels of clock genes and correlated their expression levels with clinicopathological parameters in epithelial ovarian cancer.
METHODS: The expression levels of core clock genes, per1, per2, per3, cry1, cry2, Bmal1, clock, and CKIepsilon were quantified by real-time quantitative Reverse transcription-polymerase chain reaction in 83 ovarian cancer tissues and 11 normal ovarian tissues.
RESULTS: The expression levels of per1, per2, cry2, clock, CKIepsilon in ovarian cancers were significantly lower than those in normal ovaries. In contrast, cry1 expression was highest among the eight examined clock genes, followed by per3 and Bmal1. Cry1 expression was much higher in cancer than that in normal ovaries. Localized circadian gene expression was determined in cancer cells by in situ hybridization analysis. Cry1 expression was significantly reduced in mucinous and grade 3 tumors. Bmal1 expression was also significantly reduced in mucinous adenocarcinomas as compared to other histologies. In a multivariate analysis, the combination of low cry1 expression and low Bmal1 expression was an independent prognostic factor, as well as stage and histological subtype.
CONCLUSIONS: The antiphase expression of cry1 and Bmal1 may be preserved in ovarian cancers. The combination of cry1 and Bmal1 expression might become a possible prognostic marker in epithelial ovarian cancer.

Suzuki T, Sato F, Kondo J, et al.
Period is involved in the proliferation of human pancreatic MIA-PaCa2 cancer cells by TNF-alpha.
Biomed Res. 2008; 29(2):99-103 [PubMed] Related Publications
Recent studies have found alterations to clock genes in several forms of cancer. Period (Per) gene plays an important role in the circadian system, the cell cycle, the induction of apoptosis, and DNA damage. However, the functions of Per in pancreatic cancer have not yet been elucidated. Here, we show that tumor necrosis factor-alpha (TNF-alpha) suppressed the expression of both Per1 and Per3 in MIA-PaCa2 cells, a human pancreatic cancer cell line. The levels of these proteins were 10% lower in the cells treated with 10 ng/mL TNF-alpha. Cell proliferation showed a 15%, 14%, and 16% decrease at 0.4, 2.0, and 10 ng/mL of TNF-alpha, respectively. In MTS-assays, MIA-PaCa2 cells transfected with siRNA against Per1 showed a 19% reduction in proliferation. However, the knockdown of Per3 did not significantly inhibit cell proliferation. The results suggest Per1 to be involved in the inhibition of the proliferation of MIA-PaCa2 cells by TNF-alpha.

Lin YM, Chang JH, Yeh KT, et al.
Disturbance of circadian gene expression in hepatocellular carcinoma.
Mol Carcinog. 2008; 47(12):925-33 [PubMed] Related Publications
Circadian rhythm plays an important role in the regulation of digestive system. The human circadian rhythm is controlled by at least nine circadian genes. The aims of this study are to understand the expression of the circadian genes between hepatocellular carcinoma tissues and nontumor tissues, and to explore the possible mechanism(s) contributing to the difference. We analyzed differential expression of the 9 circadian genes in 46 hepatocellular carcinoma and paired noncancerous tissues by real-time quantitative RT-PCR and immunohistochemical detection. We also tested the possible regulatory mechanism(s) by direct sequencing and methylation PCR analysis. Our results showed that decreased expression levels of PER1, PER2, PER3, CRY2, and TIM in hepatocellular carcinomas were observed. Decreased-expression of these genes was not caused by genetic mutations, but by several factors, such as promoter methylation, overexpression of EZH2 or other factors. The down expression of more circadian genes may result in disturbance of cell cycle, and it is correlated with the tumor size. Downregulation of circadian genes results in disturbance of circadian rhythm in hepatocellular carcinoma which may disrupt the control of the central pacemaker and benefit selective survival of cancerous cells and promote carcinogenesis.

Chu LW, Zhu Y, Yu K, et al.
Variants in circadian genes and prostate cancer risk: a population-based study in China.
Prostate Cancer Prostatic Dis. 2008; 11(4):342-8 [PubMed] Related Publications
Circadian genes influence a variety of biological processes that are important in prostate tumorigenesis including metabolism. To determine if variants in circadian genes alter prostate cancer risk, we genotyped five variants in five circadian genes in a population-based case-control study conducted in China (187 cases and 242 controls). These variants included CRY2 rs1401417:G>C, CSNK1E rs1005473:A>C, NPAS2 rs2305160:G>A, PER1 rs2585405:G>C and PER3 54-bp repeat length variant. Men with the cryptochrome 2 (CRY2)-variant C allele had a significant 1.7-fold increased prostate cancer risk (95% confidence interval (CI), 1.1-2.7) relative to those with the GG genotype. This risk increased to 4.1-fold (95% CI, 2.2-8.0) in men who also had greater insulin resistance (IR) as compared to men with the GG genotype and less IR. In contrast, among men with less IR, the NPAS2-variant A allele was associated with decreased prostate cancer risk (odds ratio=0.5, 95% CI, 0.3-1.0) as compared to the GG genotype. Our findings, although in need of confirmation, suggest that variations in circadian genes may alter prostate cancer risk and some biological processes may modify this effect.

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