Disturbance of circadian gene expression in hepatocellular carcinoma.
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.
Lin
Yueh-Min
YM
Department of Laboratory Medicine, Kaohsiung Medical University Hospital, Institute of Clinical Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
Chang
Julia H
JH
Yeh
Kun-Tu
KT
Yang
Ming-Yu
MY
Liu
Ta-Chih
TC
Lin
Sheng-Fung
SF
Su
Wei-Wen
WW
Chang
Jan-Gowth
JG
D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics; D002940:Circadian Rhythm / Q000235:genetics*; D056931:Cryptochromes; D005260:Female; D005420:Flavoproteins / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics; D056950:Period Circadian Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics; D055815:Young Adult
C538966:CRY2 protein, human; D018797:Cell Cycle Proteins; D056931:Cryptochromes; D005420:Flavoproteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C539022:PER1 protein, human; C421902:PER2 protein, human; C512644:PER3 protein, human; D056950:Period Circadian Proteins; C509769:TIMELESS protein, human; D014157:Transcription Factors