Aldehyde dehydrogenase 2 suppresses cirrhosis and alcohol-induced hepatocellular carcinoma via the inhibition of acetaldehyde-derived DNA damage and multiple oncogenic signaling pathways

Bin Gao, Wonhyo Seo, Yanhang Gao, Tianyi Ren, Seungjin Kim, Yong He, Dechun Feng, Junqi Niu


Objective: Hepatocellular carcinoma (HCC) is the mostcommon primary liver cancer, the fifth most common cancerand the third most common global cause of cancer relateddeaths. Chronic alcohol consumption is a well-known riskfactor for HCC. Acetaldehyde, a main metabolite of ethanoloxidation, is a very reactive compound involved in alcoholinducedliver damage. Aldehyde dehydrogenase 2 (ALDH2)is a key enzyme to detoxify produced acetaldehyde and it hasa protective role against acetaldehyde-derived DNA damagein esophageal cancer. However, the effects of ALDH2 in theprogression of HCC and the underlying mechanisms remainlargely unknown.

Methods: Three hundred patients with chronic viral hepatitisB infection were recruited to study the association of ALDH2polymorphisms and disease progression. The role of ALDH2in HCC development was studied in mouse models of HCCinduced by injection of CCl4 and alcohol.

Results: ALDH2 polymorphism is not associated with liverdisease progression from injury to cirrhosis in viral hepatitispatients, but is associated with the increased risk of HCCdevelopment in HBV cirrhotic patients with or withoutalcohol consumption. ALDH2 knockout (KO) mice weremore susceptible to chronic CCl4 plus ethanol-induced HCCas well as the progression of liver fibrosis and liver cancer.ALDH2 KO mice also had higher levels of oxidative stress/lipid peroxidation and increased DNA damage than WTmice after chronic CCl4 plus ethanol challenge. In contrast,without alcohol consumption, WT and ALDH2 KO mice hadthe same degree of liver fibrosis and liver cancer developmentafter CCl4 treatment alone. Furthermore, chronic CCl4 plusethanol challenge significantly increased extracellular vesicle(EV) formation in blood serum and in vitro hepatocyteculture. Interestingly, oxidized DNA was found in hepatocytederivedEV and the amount of oxidized DNA was significantlyincreased in ALDH2 deficient mouse blood serum andcultured medium. In vitro experiments demonstrated that theseoxidized DNA enriched EVs promoted hepatic stellate cellactivation. Finally, activation of several oncogenic signalingpathways in the liver was higher in ALDH2 KO mice than inWT mice after CCl4-plus-ethanol treatment.

Conclusions: Aldehyde dehydrogenase 2 suppresses cirrhosisand alcohol-induced hepatocellular carcinoma via the inhibitionof acetaldehyde-derived DNA damage and multiple oncogenicsignaling pathways.

DOI: 10.20892/j.issn.2095-3941.2018.S123


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