The role of ALDH2 in tumorigenesis and tumor progression: Targeting ALDH2 as a potential cancer treatment

Zhang, Hong; Fu, Liwu

doi:10.1016/j.apsb.2021.02.008

Cited by 87 publications

(76 citation statements)

References 121 publications

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“…ALDH2 (aldehyde dehydrogenase 2) is one of the major mitochondrial enzymes protecting cells from acetaldehyde toxicity. ALDH2 down-regulation has been widely reported in HCC and associated with an unfavorable outcome [ 41 , 42 ]. The gain and loss of function experiments demonstrated that ALDH2 inhibited HCC cell migration and invasion both in vitro and in vivo by modulating the redox status of cells and by activating the AMP-activated protein kinase (AMPK) signaling pathway [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

A Minimal Subset of Seven Genes Associated with Tumor Hepatocyte Differentiation Predicts a Poor Prognosis in Human Hepatocellular Carcinoma

Desoteux

Louis

Bévant

et al. 2021

Cancers

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Hepatocellular carcinoma (HCC) is a deadly cancer worldwide as a result of a frequent late diagnosis which limits the therapeutic options. Tumor progression in HCC is closely correlated with the dedifferentiation of hepatocytes, the main parenchymal cells in the liver. Here, we hypothesized that the expression level of genes reflecting the differentiation status of tumor hepatocytes could be clinically relevant in defining subsets of patients with different clinical outcomes. To test this hypothesis, an integrative transcriptomics approach was used to stratify a cohort of 139 HCC patients based on a gene expression signature established in vitro in the HepaRG cell line using well-controlled culture conditions recapitulating tumor hepatocyte differentiation. The HepaRG model was first validated by identifying a robust gene expression signature associated with hepatocyte differentiation and liver metabolism. In addition, the signature was able to distinguish specific developmental stages in mice. More importantly, the signature identified a subset of human HCC associated with a poor prognosis and cancer stem cell features. By using an independent HCC dataset (TCGA consortium), a minimal subset of seven differentiation-related genes was shown to predict a reduced overall survival, not only in patients with HCC but also in other types of cancers (e.g., kidney, pancreas, skin). In conclusion, the study identified a minimal subset of seven genes reflecting the differentiation status of tumor hepatocytes and clinically relevant for predicting the prognosis of HCC patients.

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Section: Discussionmentioning

confidence: 99%

A Minimal Subset of Seven Genes Associated with Tumor Hepatocyte Differentiation Predicts a Poor Prognosis in Human Hepatocellular Carcinoma

Desoteux

Louis

Bévant

et al. 2021

Cancers

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“…While individuals with the ALDH2*2 allele have a reduced risk of developing alcoholism, it increases their cancer risk (Crabb et al 2004;Zhang and Fu 2021). Nevertheless, this allele was found to be associated in the Japanese population with better survival (Sakaue et al 2020).…”

Section: Wider Biomedical Contextmentioning

confidence: 99%

“…In particular, the ALDH2*2 variant (rs671), which is common only in individuals of East Asian ancestry, has been intensively studied in East Asians. While individuals with the ALDH2*2 allele have a reduced risk of developing alcoholism, it increases their cancer risk (Crabb et al 2004;Zhang and Fu 2021). Nevertheless, this allele was found to be associated in the Japanese population with better survival (Sakaue et al 2020).…”

Section: Wider Biomedical Contextmentioning

confidence: 99%

Positive selection affects the human ADLH2 gene expression: genetic adaptation to alcohol consumption

Schaschl

Göllner

Morris

2021

Preprint

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ALDH2 is a key enzyme in alcohol metabolism that protects cells from acetaldehyde toxicity. Using iHS and FST statistics, we identified regulatory acting variants affecting ALDH2 gene expression under positive selection in populations of European ancestry. Several SNPs (rs3184504, rs4766578, rs10774625, rs597808, rs653178, rs847892, rs2013002) that function as eQTLs for ALDH2 in various tissues showed evidence of positive selection. Very large pairwise FST values indicated high genetic differentiation at these loci between populations of European ancestry and populations of other global ancestries. Estimating the timing of positive selection on the beneficial alleles suggests that these variants were recently adapted approximately 3000 to 3700 years ago. The derived beneficial alleles are in complete linkage disequilibrium with the derived ALDH2 promoter variant rs886205, which is associated with higher transcriptional activity. The SNPs rs4766578 and rs847892 are located in binding sequences for the transcription factor HNF4A, which is an important regulatory element of ALDH2 gene expression. In contrast to the missense variant ALDH2 rs671 (ALDH2*2), which is common only in East Asian populations and is associated with greatly reduced enzyme activity and alcohol intolerance, the beneficial alleles of the regulatory variants identified in this study are associated with increased expression of ALDH2. This suggests adaptation of Europeans to higher alcohol consumption.

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“…The relevance of this enzyme in the context of gastroenteric tumour is also given by the fact that CRCs are at times linked to high consumption of alcohol ( Ferrari et al, 2012 ; Na and Lee, 2017 ). This could in part be attributable to acetaldehyde accumulation, produced by the alcohol oxidation ( Zhang and Fu, 2021 ). Indeed, an unhealthy lifestyle with high alcohol consumption can be considered as one of the most common and important causes related to the potential development of CRCs and other significant cancers as head and neck, oesophageal and gastric ( Zhang and Fu, 2021 ).…”

Section: Nicotinamide Adenine Dinucleotide-utilizing Enzymes As Drug Targetsmentioning

confidence: 99%

Insight Into Nicotinamide Adenine Dinucleotide Homeostasis as a Targetable Metabolic Pathway in Colorectal Cancer

et al. 2021

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Tumour cells modify their cellular metabolism with the aim to sustain uncontrolled proliferation. Cancer cells necessitate adequate amounts of NAD and NADPH to support several enzymes that are usually overexpressed and/or overactivated. Nicotinamide adenine dinucleotide (NAD) is an essential cofactor and substrate of several NAD-consuming enzymes, such as PARPs and sirtuins, while NADPH is important in the regulation of the redox status in cells. The present review explores the rationale for targeting the key enzymes that maintain the cellular NAD/NADPH pool in colorectal cancer and the enzymes that consume or use NADP(H).

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The role of ALDH2 in tumorigenesis and tumor progression: Targeting ALDH2 as a potential cancer treatment

Cited by 87 publications

References 121 publications

A Minimal Subset of Seven Genes Associated with Tumor Hepatocyte Differentiation Predicts a Poor Prognosis in Human Hepatocellular Carcinoma

A Minimal Subset of Seven Genes Associated with Tumor Hepatocyte Differentiation Predicts a Poor Prognosis in Human Hepatocellular Carcinoma

Positive selection affects the human ADLH2 gene expression: genetic adaptation to alcohol consumption

Insight Into Nicotinamide Adenine Dinucleotide Homeostasis as a Targetable Metabolic Pathway in Colorectal Cancer

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