Liver expression of Nrf2-related genes in different liver diseases

BACKGROUND： The KEAP1-Nrf2 antioxidant signaling pathway is important in protecting liver from various insults. However,little is known about the expression of Nrf2-related genes in human liver in different diseases.METHODS： This study utilized normal donor liver tissues（n=35）, samples from patients with hepatocellular carcinoma（HCC, n=24）, HBV-related cirrhosis（n=27）, alcoholic cirrhosis（n=5） and end-stage liver disease（n=13）. All of the liver tissues were from the Oriental Liver Transplant Center, Beijing,China. The expressions of Nrf2 and Nrf2-related genes, including its negative regulator Kelch-like ECH-associated protein 1（KEAP1）, its targeted gene NAD（P）H-quinone oxidoreductase 1（NQO1）, glutamate-cysteine ligase catalytic subunit（GCLC） and modified subunit（GCLM）, heme oxygenase 1（HO-1） and peroxiredoxin-1（PRDX1） were evaluated. RESULTS： The expression of Nrf2 was decreased in HCC, increased in alcoholic cirrhosis and end-stage liver disease. The expression of KEAP1 was increased in all of the liver samples.The most notable finding was the increased expression of NQO1 in HCC（18-fold）, alcoholic cirrhosis（6-fold）, endstage liver disease（5-fold） and HBV-related cirrhosis（3-fold）.Peri-HCC also had 4-fold higher NQO1 m RNA as compared to the normal livers. GCLC m RNA levels were lower only in HCC, as compared to the normal livers and peri-HCC tissues.GCLM m RNA levels were higher in HBV-related cirrhosis and end-stage liver disease. HO-1 m RNA levels were increased in all liver tissues except for HCC. Peri-HCC had higher PRDX1 m RNA levels compared with HCC and normal livers.CONCLUSION： Nrf2 and Nrf2-related genes are aberrantly expressed in the liver in different diseases and the increase of NQO1 was the most notable finding, especially in HCC.

Dysregulation of metallothionein and circadian genes in human hepatocellular carcinoma

OBJECTIVE To study the dysregulation of metallothioneins(MT)and circadian genes in achieved human hepatocellular carcinoma(HCC),Peri-HCC tissues as compared to normal human livers,which may open up a new avenue for targeting circadian clock to prevent and treatment of HCC.METHODS Total RNA was extracted,purified,and reverse transcribed.Realtime quantitative polymerase chain reaction(RT-q PCR)was performed to determine the expression of genes of metallothionein-1(MT-1),MT-2,and metal transcription factor-1(MFT-1)and circadian clock genes including core clock genes,circadian locomotor output cycles kaput(Clock)and brain and muscle Arnt-like protein 1(Bmal1),the clock feedback control genes,period(Per1,Per2)and cryptochrome(Cry1,Cry2),and clock target genes,nuclear orphan receptor factor protein(Nr1d1)and D-box-binding protein(Dbp)in human HCC,Peri-HCC and normal livers.RESULTS The expression of MT-1,MT-2,MFT-1 in human HCC was decreased,which were previously shown to have circadian rhythms.Similarly,the expression of the core clock genes(Bmal1,Clock),the clock feedback genes(Per1,Per2,Cry1and Cry2)was decreased in human HCC,as compared to Peri-HCC and normal livers.However,the expression of clock target genes(Nr1d1and Dbp)was increased in human HCC,as compared to Peri-HCC and normal livers.CONCLUSION These data clearly demonstrated the dysregulation of MTs and circadian clock genes in HCC,which could provide new insights into the relationship of circadian clock disruption and loss of MT in hepatocarcinogenesis,and could help a new strategy of targeting MT and circadian clock in the prevention and treatment of HCC.