Aldehyde dehydrogenase‐2 (ALDH2) opposes hepatocellular carcinoma progression by regulating AMP‐activated protein kinase signaling in mice

Hou, Guoqing; Chen, Lei; Liu, Gang; Li, Liang; Yang, Yuan; Yan, He‐Xin; Zhang, Hui‐Lu; Tang, Jing; Yang, Ying; Lin, Xiao; Chen, Xin; Luo, Gui; Zhu, Yanjing; Tang, Shanhua; Zhang, Jin; Liu, Hui; Gu, Qing; Zhao, Lan‐Juan; Li, Yixue; Liu, Lei; Zhou, Weiping; Wang, Hongyang

doi:10.1002/hep.29006

Cited by 56 publications

(61 citation statements)

References 41 publications

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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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“…Proteomic clustering identified three subgroups, among which, the metabolism subgroup was characterized by the highest expression levels of proteins related to metabolism and liver function, including ALDH1A1, ALDH1A2, ALDH2, ALDH4A1, and ALDH9A1 [92]. In terms of prognosis, a lower ALDH2 level was a poor prognosticator following primary resection, coincident with older age, embolus, larger tumor size, extrahepatic metastasis and microvascular invasion in HCC patients [13]. Furthermore, a correlation of higher ALDH1B1 and ALDH1L1 gene expression with better clinical outcomes was noted in HBV-related HCC patients [16,93].…”

Section: Aldh and Hccmentioning

confidence: 99%

“…Three isotype genes of ALDH1 (ALDH1A1, ALDH1A2, and ALDH1A3) are located on 9q21.13, 15q21.3, and 15q26.3, respectively [13]. ALDH1 is expressed in both stem cells and differentiated cells.…”

Section: Aldh Genes and Polymorphismsmentioning

confidence: 99%

“…A dose-dependent association between the cumulative amount of alcohol consumption over time and HCC risk in individuals with the ALDH2*1/*2 or ALDH2*2/*2 genotype was reported based on a comparison of a HCC cohort of 208 cases and a control cohort of 208 control cases conducted in Jiangsu, China [55]. Moreover, a study of independent HCC cohorts suggested a negative correlation between ALDH2 expression and predisposition to malignant HCC [13]. However, the correlation of the ALDH2*1/*1 genotype with increased HCC risk in HBV-positive patients with cirrhosis was suggested based on an analysis of 4155 Figure 2.…”

Section: Aldh and Hccmentioning

confidence: 99%

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Aldehyde Dehydrogenase, Liver Disease and Cancer

Wang

et al. 2020

Int. J. Biol. Sci.

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Acetaldehyde dehydrogenase 2 (ALDH2) is the key enzyme responsible for metabolism of the alcohol metabolite acetaldehyde in the liver. In addition to conversion of the acetaldehyde molecule, ALDH is also involved in other cellular functions. Recently, many studies have investigated the involvement of ALDH expression in viral hepatitis, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, and liver cancer. Notably, ALDH2 expression has been linked with liver cancer risk, as well as pathogenesis and prognosis, and has emerged as a promising therapeutic target. Of note, approximately 8% of the world's population, and approximately 30-40% of the population in East Asia carry an inactive ALDH2 gene. This review summarizes new progress in understanding tissue-specific acetaldehyde metabolism by ALDH2 as well as the association of ALDH2 gene polymorphisms with liver disease and cancer. New research directions emerging in the field are also briefly discussed.

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“…19 Moreover, a previous study revealed that the AMPK signaling pathway was blocked in HCC. 20 AMPK silencing has been found to prevent apoptosis upon N6-isopentenyladenosine treatment, while basal autophagosome turnover is repressed as a result of unprenylated Rab7. 21 Based on the previously-mentioned literature, we hypothesized that miR-519d was involved in HCC via the AMPK signaling pathway by controlling Rab10.…”

Section: Introductionmentioning

confidence: 99%

<p>microRNA-519d Induces Autophagy and Apoptosis of Human Hepatocellular Carcinoma Cells Through Activation of the AMPK Signaling Pathway via Rab10</p>

Zhang¹,

Pan²,

Yu³

et al. 2020

CMAR

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Background and Aim: Hepatocellular carcinoma (HCC) is a type of cancer with high mortality rates. The overexpression of microRNA-519d (miR-519d) has been explored in different types of cancers, which could significantly help suppress cancer development. This study aimed to investigate the interaction of miR-519d with its target gene, Rab10, as well as its effects on cell proliferation and autophagy in HCC cells through modulation of the AMPK signaling pathway. Methods: Microarray analysis was used to analyze the differentially expressed genes in HCC, and the target genes of the screened-out miRNA were predicted and verified. The expression of miR-519d and Rab10, AMPK signaling pathway-related proteins, apoptosisand autophagy-related proteins was determined by RT-qPCR and Western blot analysis in HCC tissues and cell lines. Lastly, the effects of miR-519d and Rab10 in HCC cell proliferation, apoptosis, and mouse tumour xenograft in vivo were examined through gainand loss-of-function experiments. Results: MiR-519d was down-regulated and Rab10 was upregulated in HCC tissues and cell lines. Overexpression of miR-519d decreased the expression of Rab10, mTOR, and Bcl-2, but increased the expression of Bax, Beclin1, Atg5, and p53. Upregulated miR-519d and downregulated Rab10 expression suppressed cell proliferation and induced cell apoptosis and autophagy in HCC cells. Finally, upregulation of miR-519d inhibited tumour growth in vivo. Conclusion: The result obtained in this study indicates that up-regulation of miR-519d inhibits proliferation and promotes apoptosis and autophagy of HCC cells through activation of the AMPK signaling pathway via downregulating Rab10, which provides a potential target for the treatment of HCC.

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Aldehyde dehydrogenase‐2 (ALDH2) opposes hepatocellular carcinoma progression by regulating AMP‐activated protein kinase signaling in mice

Cited by 56 publications

References 41 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

Aldehyde Dehydrogenase, Liver Disease and Cancer

<p>microRNA-519d Induces Autophagy and Apoptosis of Human Hepatocellular Carcinoma Cells Through Activation of the AMPK Signaling Pathway via Rab10</p>

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