Roles of defective ALDH2 polymorphism on liver protection and cancer development

Matsumoto, Akiko; Thompson, David C.; Chen, Ying; Kitagawa, Kyoko; Vasiliou, Vasilis

doi:10.1007/s12199-016-0579-2

Cited by 23 publications

(19 citation statements)

References 74 publications

(86 reference statements)

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“…We identified three clinical prognostic-related editing sites, which can also provide predictive values in HBV-/HCV-infected patients and non-alcoholic fatty liver disease patients, including editing sites in ALDH2 (chr12:111811793, A-to-I RNA editing), CNTNAP3B (chr9:41929326, C-to-T RNA editing), and CBWD5 (chr9:65675990, T-to-G RNA editing), of which ALDH2 is an HCC-related editing gene with high frequency (six HCC loss editing sites locates on the ALDH2 gene region). Interestingly, multiple studies revealed that ALDH2 is highly correlated with the pathogenic mechanism, risk, and survival of liver cancer patients, including HCC (47)(48)(49)(50). Functional annotation suggested that these HCC-related editing sites with functional consequence are widely involved in liver cancer-associated genes, especially tumor suppressive genes, and cancer-associated pathways.…”

Section: Discussionmentioning

confidence: 99%

Genomic Identification of RNA Editing Through Integrating Omics Datasets and the Clinical Relevance in Hepatocellular Carcinoma

Chen

Wang

et al. 2020

Front. Oncol.

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RNA editing is a widespread post-transcriptional mechanism to introduce single nucleotide changes to RNA in human cancers. Here, we characterized the global RNA editing profiles of 373 hepatocellular carcinoma (HCC) and 50 adjacent normal liver samples from The Cancer Genome Atlas (TCGA) and revealed that most editing events tend to occur in minor percentage of samples with moderate editing degrees (20-30%). Moreover, these RNA editing prefer to be A-to-I RNA editing in protein coding genes, especially in 3 ′ UTR regions. Considering the association between DNA mutation and RNA editing, our analysis found that RNA editing maybe a complementary event for DNA mutation of HCC risk genes in HCC patients. We next identified 454 HCC-related editing sites, and many locate on the same genes with the same editing patterns. The functional consequences of editing revealed 2,086 functional editing sites and demonstrated that most editing in coding regions are non-synonymous variations. Furthermore, our results showed that editing in the 3 ′ UTR regions tend to influence miRNA-target binding, and the editing degree seems to be negatively correlated with gene expression. Finally, we found that 46 HCC-related editing sites with consequence are able to distinguish the prognosis differences of HCC patients, suggesting their clinical relevance. Together, our results highlight RNA editing as a valuable molecular resource for investigating HCC mechanisms and clinical treatments.

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Section: Discussionmentioning

confidence: 99%

Genomic Identification of RNA Editing Through Integrating Omics Datasets and the Clinical Relevance in Hepatocellular Carcinoma

Chen

Wang

et al. 2020

Front. Oncol.

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“…It was widely reported that the activation of aldehyde dehydrogenase (ALDH)2 has a number of implications on the brain, heart, lung, liver injury and cancer ( 5 , 6 ). The previous studies identified that the activation of ALDH2 can attenuate diabetes-induced oxidative stress and myocardial injury as well as inhibiting apoptosis ( 7 – 9 ).…”

Section: Introductionmentioning

confidence: 99%

Alterations in necroptosis during ALDH2‑mediated protection against high glucose‑induced H9c2 cardiac cell injury

et al. 2018

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The aim of the present study was to investigate whether necroptosis occurs in high glucose (HG)-induced H9c2 cardiac cell injury and whether the activation of aldehyde dehydrogenase 2 (ALDH2) can inhibit necroptosis. H9c2 cardiac cells were treated with 35 mM glucose to establish a HG-induced cell injury model. Alda-1 (20 µM), a specific activator of ALDH2 and necrostatin-1 (Nec-1, 100 µM), an inhibitor of necroptosis were used to treat H9c2 cardiac cells under HG conditions. Cell viability was measured using a Cell Counting Kit-8 assay and reactive oxygen species (ROS) generation was measured by the dihydroethidium staining method. ALDH2 activity was measured at 450 nm. The mRNA and protein expression of ALDH2, necroptosis-associated genes, receptor-interacting protein (RIP)1, RIP3 and mixed lineage kinase domain like pseudokinase (MLKL), were analyzed by reverse transcription-quantitative polymerase chain reaction and western blotting. The expression of cleaved caspase-3 protein was also examined by western blotting. The results demonstrated that under HG conditions, cell viability, ALDH2 activity, mRNA and protein expression were decreased. Furthermore, ROS generation, mRNA and protein expression of RIP1, RIP3, MLKL and the protein expression of cleaved caspase-3 were increased. Treatment with Alda-1 or Nec-1 attenuated HG-induced downregulation of ALDH2 activity, mRNA and protein expression. In addition, RIP1, RIP3, MLKL mRNA, and protein expression were downregulated. Furthermore, Alda-1 but not Nec-1 decreased cleaved caspase-3 protein expression. Collectively these data indicated that activation of ALDH2 protected H9c2 cardiac cells against HG-induced injury, partly by inhibiting the occurrence of necroptosis.

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“…Human subjects carrying a defective allele of the ALDH2 gene ( ALDH2 * 2 allele) have a greatly reduced capacity (10–45% normal in heterozygotes and 1–5% normal in homozygotes) to metabolize acetaldehyde [70]. Epidemiological studies have revealed these individuals to be highly susceptible to the development of gastrointestinal cancers following excessive alcohol consumption [71]. Following chronic ethanol consumption, acetaldehyde-DNA adducts are elevated to a greater extent in the liver and stomach of Aldh2 KO mice than in wild-type mice [72, 73].…”

Section: Alcohol-mediated Carcinogenesismentioning

confidence: 99%

Glutathione and Transsulfuration in Alcohol-Associated Tissue Injury and Carcinogenesis

Chen

Han

Matsumoto

et al. 2018

Advances in Experimental Medicine and Biology

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Glutathione (GSH) is the most abundant non-protein thiol, attaining cellular concentrations in the millimolar range. GSH functions to protect cells against endogenous and exogenous electrophiles. In addition, GSH serves as a cofactor for the GSH peroxidase family of enzymes which metabolize H2O2 as well as lipid peroxides. Through the action of glutathione S-transferase family of enzymes, GSH is conjugated to a variety of electrophilic endogenous compounds and exogenous chemicals, and thereby facilitates their efficient and safe elimination. Through the transsulfuration pathway, GSH biosynthesis is metabolically linked with cellular methylation, which is pivotal for epigenetic gene regulation. Accumulating evidence suggests that the underlying mechanisms of alcohol-associated tissue injury and carcinogenesis involve: (i) generation of the electrophilic metabolite acetaldehyde, (ii) induction of CYP2E1 leading to the formation of reactive oxygen species and pro-carcinogen activation, and (iii) nutritional deficiencies, such as methyl groups, resulting in enhanced susceptibility to cancer development. In this context, clinical and experimental investigations suggest an intimate involvement of GSH and related enzymes in the development of alcohol-induced pathological conditions. The aim of this review is to provide an overview of the GSH biosynthesis, cellular transsulfuration/transmethylation pathways, and their implications in the pathogenesis and treatment of alcohol-related disease and cancer.

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Roles of defective ALDH2 polymorphism on liver protection and cancer development

Abstract: Because serum transaminases elevate alcohol dose dependently as a consequence of liver injury, they serve as useful biological markers of excessive drinking.

Cited by 23 publications

References 74 publications

Genomic Identification of RNA Editing Through Integrating Omics Datasets and the Clinical Relevance in Hepatocellular Carcinoma

Genomic Identification of RNA Editing Through Integrating Omics Datasets and the Clinical Relevance in Hepatocellular Carcinoma

Alterations in necroptosis during ALDH2‑mediated protection against high glucose‑induced H9c2 cardiac cell injury

Glutathione and Transsulfuration in Alcohol-Associated Tissue Injury and Carcinogenesis

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