Mechanisms of alcohol-induced hepatocellular carcinoma

Sidharthan, Sreetha; Kottilil, Shyam

doi:10.1007/s12072-013-9494-4

Cited by 25 publications

(21 citation statements)

References 56 publications

(55 reference statements)

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“…1 There are multiple risk factors associated with the development of HCC, including viral hepatitis, aflatoxin exposure and excessive alcohol abuse. 2 , 3 , 4 Currently, oxidative stress induced via abnormal mitochondrial regulation has also been proposed as an important factor in the pathogenesis of HCC. 5 , 6 …”

Section: Introductionmentioning

confidence: 99%

Aspartate β-hydroxylase disrupts mitochondrial DNA stability and function in hepatocellular carcinoma

et al. 2017

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The mechanism of aberrant mitochondrial genome and function in hepatocellular carcinoma (HCC) remains largely unknown. Our previous study demonstrated an increased expression of aspartate β-hydroxylase (ASPH) in HCC tissues, which was associated with tumor invasiveness and a worse prognosis. Currently, we unexpectedly observed the presence of ASPH in purified mitochondrial protein fraction. In addition, immunostaining of both exogenously and endogenously expressed ASPH showed a colocalization with mitochondrial biomarkers. This study aimed to investigate whether the mitochondrial ASPH is involved in mitochondrial malfunction in HCC. Our results showed that ASPH overexpression in HCC tissues was correlated with decreased copy numbers of displacement loop (D-loop) and NADH dehydrogenase subunit 1 (ND-1) and enhanced D-loop mutation, suggesting the disrupted mitochondrial DNA (mtDNA) stability. The reduced mtDNA copy numbers were associated with aggressive clinicopathological features of HCC. The loss of mtDNA integrity induced by enforced expression of ASPH was accompanied with mitochondrial dysfunction, which was characterized by the aberrant mitochondrial membrane potential, decreased ATP generation and enhanced reactive oxygen species. In contrast, knocking down ASPH by siRNA in HCC cell lines showed the opposite impact on mtDNA integrity and function. Mass spectrometry and co-immunoprecipitation further identified that ASPH interacted with histone H2A member X (H2AX). ASPH overexpression diminished the interaction between H2AX and mitochondrial transcription factor A (mtTFA), an important DNA-binding protein for mtDNA replication, which then reduced the binding of mtTFA to D-loop region. Collectively, our results demonstrate that ASPH overexpression disrupts the mtDNA integrity through H2AX–mtTFA signal, thereby affecting mitochondrial functions in HCC.

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Section: Introductionmentioning

confidence: 99%

Aspartate β-hydroxylase disrupts mitochondrial DNA stability and function in hepatocellular carcinoma

et al. 2017

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“…HCC is one of the most common cancers and is the second leading cause of cancer-related mortality worldwide [ 1 ]. The risk factors accounting for HCC development include chronic HBV infection [ 2 ], hepatitis C virus infection [ 3 ], excessive consumption of alcohol [ 4 ], and aflatoxin exposure [ 5 ]. Among them, HBV is a major etiological agent of HCCs.…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic profiling of long non-coding RNAs in hepatitis B virus-related hepatocellular carcinoma

et al. 2017

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Long non-coding RNAs (lncRNAs) have been reported to be involved in the development and progression of hepatocellular carcinoma (HCC). However, few studies have focus on the dyregulation and the role of lncRNAs in HBV-related HCC. We performed a comprehensive analysis of lncRNAs expression profile in HBV-related HCC tissues samples using deep sequencing. We revealed that a total of 1242 lncRNA transcripts (983 up-regulated and 259 down-regulated) and 1841 mRNA transcripts were significantly differentially expressed in HBV-related HCC patients. Pathway and gene ontology analysis showed that they are involved in the biological process related to HCC development by cis-regulation of co-expressed protein-coding genes. 10 candidate lncRNAs were selected and validated with quantitative real-time PCR analysis. Furthermore, we found that one of most down-regulated lncRNAs, n346077, could suppress HCC cells invasion and migration in vitro. Our findings provide an overview of aberrantly expressed lncRNAs in HBV-related HCC and will be useful for further functional studies of lncRNAs in HBV-related pathogenesis.

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“…The major mechanisms of alcohol-induced HCC include pathways of ethanol metabolism, alcohol-induced oxidative stress and hypomethylation of DNA, and interplay of alcohol with iron elevation, retinoid metabolism, the immune system, inflammatory pathways, and neoangiogenesis. 31,32 The understanding of hepatocarcinogenesis in NASH although still evolving, is believed to originate from deregulated one-carbon metabolism, nuclear factor kB proteins, phosphatase and tensin homolog (PTEN), microRNA instability and telomere shortening. 33 Consistent with published literature our patients with NASH-HCC were significantly older than patients with ASH-HCC with most of the patients in NASH-HCC group in their 7th decade of life whereas patients in ASH-HCC group were a decade younger.…”

Section: Figure 2 Kaplan Meier Overall Survival Analysis Between Thementioning

confidence: 99%

Comparisons between non-alcoholic steatohepatitis and alcohol-related hepatocellular carcinoma

et al. 2020

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Background/Aims: Non-alcoholic liver disease and alcoholic liver disease begin as simple steatosis that may progress to steatohepatitis and ensuing liver-related complications such as cirrhosis and hepatocellular carcinoma (HCC). We explored differences in characteristics between non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis-related (ASH) HCC.Methods: NASH and ASH patients were identified from our department’s prospective HCC database. A total of 54 and 45 patients met predefined inclusion and exclusion criteria for the NASH-HCC and ASH-HCC groups, respectively. Clinical, biochemical and tumor characteristics were studied.Results: NASH-HCC patients were older compared to ASH-HCC patients (72±9 vs. 66±9 years, P<0.001) and less male predominant (65% vs. 98%, P<0.001). Prevalence of diabetes mellitus (78% vs. 36%, P<0.001) and hypertension (80% vs. 58%, P<0.001) were significantly higher in the NASH-HCC group. Liver function tests and Child-Pugh scores were similar. There were no differences in alpha-fetoprotein level, lesions found at diagnosis (unifocal/multifocal) or prevalence of portal vein invasion. In both groups, almost half of the patients were in TNM stage 4 at the time of diagnosis and more than 50% of patients were not suitable for any therapy. Median survival in the NASH-HCC and ASH-HCC groups were 13 and 7 months respectively (P=0.113).Conclusions: Despite significant differences in demography of the NASH-HCC and ASH-HCC groups, liver and tumor characteristics were comparable. Most patients were diagnosed late and were not amenable to curative or locoregional therapies. Better characterization of patients with NASH and ASH at risk of HCC is necessary to optimize screening, surveillance, and management strategies.

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Mechanisms of alcohol-induced hepatocellular carcinoma

Cited by 25 publications

References 56 publications

Aspartate β-hydroxylase disrupts mitochondrial DNA stability and function in hepatocellular carcinoma

Aspartate β-hydroxylase disrupts mitochondrial DNA stability and function in hepatocellular carcinoma

Transcriptomic profiling of long non-coding RNAs in hepatitis B virus-related hepatocellular carcinoma

Comparisons between non-alcoholic steatohepatitis and alcohol-related hepatocellular carcinoma

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