한빛사 논문
Wonhyo Seo1,a, Yanhang Gao1,2,a, Yong He1, Jing Sun2, Hongqin Xu2, Dechun Feng1, Seol Hee Park1, Young-Eun Cho3,4, Adrien Guillot1, Tianyi Ren1, Ruihong Wu2, Jingyun Wang2, Seung-Jin Kim1, Seonghwan Hwang1, Suthat Liangpunsakul5,6,7, Yingzi Yang8, Junqi Niu2, Bin Gao1,*
1 Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
2 Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun 130021, China
3 Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
4 Department of Food and Nutrition, Andong National University, Andong, South Korea
5 Division of Gastroenterology and Hepatology, Department of Medicine
6 Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis, IN, USA
7 Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA
8 Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA
*Corresponding author
a Wonhyo Seo and Yanhang Gao contributed equally to this work.
Abstract
Background & Aims
Excessive alcohol drinking is one of the major causes of hepatocellular carcinoma (HCC). Approximately 30-40% Asian population are deficient for aldehyde dehydrogenase 2 (ALDH2), a key enzyme to detoxify the ethanol metabolite acetaldehyde. However, how ALDH2 deficiency affects alcohol-related HCC remains obscure.
Methods
ALDH2 polymorphism in 646 patients with viral hepatitis B (HBV) infection with or without alcohol drinking was studied. A new model of HCC induced by chronic carbon tetrachloride (CCl4) and alcohol administration was developed and studied in three lines of Aldh2-deficient mice: including Aldh2 global knockout (KO) mice, Aldh2*1/*2 knock-in mutant mice, and liver-specific Aldh2 KO mice.
Results
We demonstrated that ALDH2 deficiency was not associated with liver disease progression but was associated with an increased risk of HCC development in cirrhotic HBV patients with excessive alcohol consumption. The mechanisms underlying HCC development associated with cirrhosis and alcohol consumption were studied in Aldh2-deficient mice. We found that all three lines of Aldh2-deficient mice were more susceptible to CCl4 plus alcohol-associated liver fibrosis and HCC development. Furthermore, our results from in vivo and in vitro mechanistic studies revealed that after CCl4 plus ethanol exposure, Aldh2-deficient hepatocytes produced a large amount of harmful oxidized mtDNA via extracellular vesicles (EVs), which were then transferred into neighboring HCC cells and together with acetaldehyde activated multiple oncogenic pathways (JNK, STAT3, BCL-2, and TAZ), thereby promoting HCC.
Conclusions
ALDH2 deficiency is associated with an increased risk of alcohol related-HCC development from fibrosis in patients and in mice. Mechanistic studies reveal a novel mechanism that Aldh2-deficient hepatocytes promote alcohol-associated HCC by transferring harmful oxidized mtDNA-enriched EVs into HCC and subsequently activating multiple oncogenic pathways in HCC.
Lay Summary
Alcoholics with ALDH2 polymorphism have an increased risk of digestive track cancer development, however, the link between ALDH2 deficiency and HCC development has not been well established. In this study, we show that ALDH2 deficiency exacerbates alcohol-associated HCC development both in patients and mouse models. Mechanistic studies revealed that after chronic alcohol exposure, Aldh2-deficient hepatocytes produce a large amount of harmful oxidized mitochondrial DNA via extracellular vesicles, which can be delivered into neighboring HCC cells and subsequently activate multiple oncogenic pathways, thereby promoting HCC.
Keywords : Aldehyde dehydrogenase 2; Ethanol; Acetaldehyde; Hepatocellular carcinoma; Cirrhosis; Extracellular vesicles; HBV; TAZ
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