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서원효
서원효 (Wonhyo Seo) 저자 이메일 보기
National Institutes of Health
 
조회 844  인쇄하기 주소복사 트위터 공유 페이스북 공유 
ALDH2 deficiency promotes alcohol-associated liver cancer by activating oncogenic pathways via oxidized DNA enriched extracellular vesicles
열기 Authors and Affiliations

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

논문정보
- 형식: Research article
- 게재일: 2019년 07월 (BRIC 등록일 2019-07-09)
- 연구진: 국내+국외 연구진
- 분야: Medicine
  댓글 1
회원작성글 vetknu  (2019-07-23 13:28)
늦었지만 논문 축하드리며, 앞으로 더 좋은 연구 기대하겠습니다.
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