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Article: ALDH2(E487K) mutation increases protein turnover and promotes murine hepatocarcinogenesis

TitleALDH2(E487K) mutation increases protein turnover and promotes murine hepatocarcinogenesis
Authors
KeywordsLiver cancer
Asian flush
ALDH2
Alcohol metabolism
2 polymorphism
Mouse model
Issue Date2015
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2015, v. 112, n. 29, p. 9088-9093 How to Cite?
AbstractMitochondrial aldehyde dehydrogenase 2 (ALDH2) in the liver removes toxic aldehydes including acetaldehyde, an intermediate of ethanol metabolism. Nearly 40% of East Asians inherit an inactive ALDH2∗2 variant, which has a lysine-for-glutamate substitution at position 487 (E487K), and show a characteristic alcohol flush reaction after drinking and a higher risk for gastrointestinal cancers. Here we report the characterization of knockin mice in which the ALDH2(E487K) mutation is inserted into the endogenous murine Aldh2 locus. These mutants recapitulate essentially all human phenotypes including impaired clearance of acetaldehyde, increased sensitivity to acute or chronic alcohol-induced toxicity, and reduced ALDH2 expression due to a dominant-negative effect of the mutation. When treated with a chemical carcinogen, these mutants exhibit increased DNA damage response in hepatocytes, pronounced liver injury, and accelerated development of hepatocellular carcinoma (HCC). Importantly, ALDH2 protein levels are also significantly lower in patient HCC than in peritumor or normal liver tissues. Our results reveal that ALDH2 functions as a tumor suppressor by maintaining genomic stability in the liver, and the common human ALDH2 variant would present a significant risk factor for hepatocarcinogenesis. Our study suggests that the ALDH2∗2 allele-alcohol interaction may be an even greater human public health hazard than previously appreciated.
Persistent Identifierhttp://hdl.handle.net/10722/292896
ISSN
2023 Impact Factor: 9.4
2023 SCImago Journal Rankings: 3.737
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorJin, Shengfang-
dc.contributor.authorChen, Jiang-
dc.contributor.authorChen, Lizao-
dc.contributor.authorHisten, Gavin-
dc.contributor.authorLin, Zhizhong-
dc.contributor.authorGross, Stefan-
dc.contributor.authorHixon, Jeffrey-
dc.contributor.authorChen, Yue-
dc.contributor.authorKung, Charles-
dc.contributor.authorChen, Yiwei-
dc.contributor.authorFu, Yufei-
dc.contributor.authorLu, Yuxuan-
dc.contributor.authorLin, Hui-
dc.contributor.authorCai, Xiujun-
dc.contributor.authorYang, Hua-
dc.contributor.authorCairns, Rob A.-
dc.contributor.authorDorsch, Marion-
dc.contributor.authorSu, Shinsan M.-
dc.contributor.authorBiller, Scott-
dc.contributor.authorMak, Tak W.-
dc.contributor.authorCang, Yong-
dc.date.accessioned2020-11-17T14:57:27Z-
dc.date.available2020-11-17T14:57:27Z-
dc.date.issued2015-
dc.identifier.citationProceedings of the National Academy of Sciences of the United States of America, 2015, v. 112, n. 29, p. 9088-9093-
dc.identifier.issn0027-8424-
dc.identifier.urihttp://hdl.handle.net/10722/292896-
dc.description.abstractMitochondrial aldehyde dehydrogenase 2 (ALDH2) in the liver removes toxic aldehydes including acetaldehyde, an intermediate of ethanol metabolism. Nearly 40% of East Asians inherit an inactive ALDH2∗2 variant, which has a lysine-for-glutamate substitution at position 487 (E487K), and show a characteristic alcohol flush reaction after drinking and a higher risk for gastrointestinal cancers. Here we report the characterization of knockin mice in which the ALDH2(E487K) mutation is inserted into the endogenous murine Aldh2 locus. These mutants recapitulate essentially all human phenotypes including impaired clearance of acetaldehyde, increased sensitivity to acute or chronic alcohol-induced toxicity, and reduced ALDH2 expression due to a dominant-negative effect of the mutation. When treated with a chemical carcinogen, these mutants exhibit increased DNA damage response in hepatocytes, pronounced liver injury, and accelerated development of hepatocellular carcinoma (HCC). Importantly, ALDH2 protein levels are also significantly lower in patient HCC than in peritumor or normal liver tissues. Our results reveal that ALDH2 functions as a tumor suppressor by maintaining genomic stability in the liver, and the common human ALDH2 variant would present a significant risk factor for hepatocarcinogenesis. Our study suggests that the ALDH2∗2 allele-alcohol interaction may be an even greater human public health hazard than previously appreciated.-
dc.languageeng-
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of America-
dc.subjectLiver cancer-
dc.subjectAsian flush-
dc.subjectALDH2-
dc.subjectAlcohol metabolism-
dc.subject2 polymorphism-
dc.subjectMouse model-
dc.titleALDH2(E487K) mutation increases protein turnover and promotes murine hepatocarcinogenesis-
dc.typeArticle-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1073/pnas.1510757112-
dc.identifier.pmid26150517-
dc.identifier.pmcidPMC4517197-
dc.identifier.scopuseid_2-s2.0-84937838755-
dc.identifier.volume112-
dc.identifier.issue29-
dc.identifier.spage9088-
dc.identifier.epage9093-
dc.identifier.eissn1091-6490-
dc.identifier.isiWOS:000358225100080-
dc.identifier.issnl0027-8424-

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