Dysregulation of metallothionein and circadian genes in human hepatocellular carcinoma

Dec 21, 2016Chronobiology international

Imbalance of metal-binding and body clock genes in human liver cancer

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Abstract

In a study of 24 human hepatocellular carcinoma (HCC) samples, metallothionein-1, metallothionein-2, and metal transcription factor-1 were significantly downregulated compared to peri-HCC and normal liver tissues.

Metallothioneins are associated with hepatocellular carcinoma and normally exhibit circadian rhythms.
Core circadian clock genes, Clock and Bmal1, showed a dramatic decrease in expression in HCC tissues.
Feedback control genes related to the circadian clock, such as Per1, Per2, Cry1, and Cry2, were also downregulated in HCC.
In contrast, clock target genes Nr1d1 and Dbp were upregulated in HCC compared to peri-HCC and normal tissues.
Peri-HCC tissues exhibited mild alterations in the expression of metallothioneins and circadian clock genes.

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Hepatocellular carcinoma (HCC) is the major threat to human health, and disruption of circadian clock genes is implicated in hepatocarcinogenesis. This study examined the dysregulation of metallothioneins and circadian genes in achieved human HCC (n = 24), peri-HCC tissues (n = 24) as compared with normal human livers (n = 36). Total RNA was extracted and reverse transcribed. Real-time RT-qPCR was performed to determine the expression of genes of interest. The results demonstrated the downregulation of metallothionein-1 (MT-1), MT-2, and metal transcription factor-1 (MFT-1) in human HCC as compared with Peri-HCC and normal tissues. MTs are a biomarker for HCC and have typical circadian rhythms; the expression of major circadian clock genes was also determined. HCC produced a dramatic decrease in the expression of core clock genes, circadian locomotor output cycles kaput (Clock) and brain and muscle Arnt-like protein 1 (Bmal1), and decreased the expression of the clock feedback control genes, Periods (Per1, Per2) and Cryptochromes (Cry1, Cry2). On the other hand, the expression of clock target genes nuclear orphan receptor factor protein (Nr1d1) and D-box-binding protein (Dbp) was upregulated as compared with Peri-HCC and normal livers. Peri-HCC also had mild alterations in these gene expressions. In summary, the present study clearly demonstrated the dysregulation of MTs and circadian clock genes in human HCC, which could provide the information of targeting MT and circadian clock in HCC management.

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Dysregulation of metallothionein and circadian genes in human hepatocellular carcinoma

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