Liver damage and senescence increases in patients developing hepatocellular carcinoma

Rey, Silvia; Quintavalle, Cristina; Burmeister, Katharina; Calabrese, Diego; Schlageter, Manuel; Quagliata, Luca; Cathomas, Gieri; Diebold, Joachim; Molinolo, Alfredo A.; Heim, Markus H.; Terracciano, Luigi; Matter, Matthias S.

doi:10.1111/jgh.13717

Cited by 16 publications

(9 citation statements)

References 23 publications

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“…The top 50 significantly up-regulated and down-regulated genes were listed in Figure 2 A. KEGG pathway enrichment analysis of the most significant up-regulated genes showed that the top 5 enriched pathway is cell cycle, cellular senescence, melanoma, p53 signaling pathway, and ECM-receptor interaction. All of these pathways were reported with important roles in cancer 32 - 35 (Figure 2 B). Whereas the top 5 KEGG pathway enriched in the down-regulated genes, including valine, leucine and isoleucine degradation, retinol metabolism, PPAR signaling pathway, fatty acid degradation and complement and coagulation cascades, also have been studied to be important pathways involved in tumor growth and metastasis (Figure 2 B and Table S2 ) 36 - 39 .…”

Section: Resultsmentioning

confidence: 90%

Development Of A Three-Gene Prognostic Signature For Hepatitis B Virus Associated Hepatocellular Carcinoma Based On Integrated Transcriptomic Analysis

Yao¹,

Lü²,

Shao

et al. 2018

J. Cancer

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Integration of public genome-wide gene expression data together with Cox regression analysis is a powerful weapon to identify new prognostic gene signatures for cancer diagnosis and prognosis. Hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC), however, it remains largely unknown about the specific gene prognostic signature of HBV-associated HCC. Using Robust Rank Aggreg (RRA) method to integrate seven whole genome expression datasets, we identified 82 up-regulated genes and 577 down-regulated genes in HBV-associated HCC patients. Combination of several enrichment analysis, univariate and multivariate Cox proportional hazards regression analysis, we revealed that a three-gene (SPP2, CDC37L1, and ECHDC2) prognostic signature could act as an independent prognostic indicator for HBV-associated HCC in both the discovery cohort and the internal testing cohort. Gene set enrichment analysis showed that the high-risk group with lower expression levels of the three genes was enriched in bladder cancer and cell cycle pathway, whereas the low-risk group with higher expression levels of the three genes was enriched in drug metabolism-cytochrome P450, PPAR signaling pathway, fatty acid and histidine metabolisms. This indicates that patients of HBV-associated HCC with higher expression of these three genes may preserve relatively good hepatic cellular metabolism and function, which may also protect HCC patients from persistent drug toxicity in response to various medication. Our findings suggest a three-gene prognostic model that serves as a specific prognostic signature for HBV-associated HCC.

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Section: Resultsmentioning

confidence: 90%

Development Of A Three-Gene Prognostic Signature For Hepatitis B Virus Associated Hepatocellular Carcinoma Based On Integrated Transcriptomic Analysis

Yao¹,

Lü²,

Shao

et al. 2018

J. Cancer

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“…It is possible that disruption of this process might allow for reduced viral replication and immune clearance of an often chronic and damaging infection. In addition, studies have demonstrated higher levels of cellular senescence at the hepatocyte level leading to an increased risk of HCC, with this being compounded by the impaired clearance of said senescent hepatocytes by immune cells 31,32. These findings demonstrate the complex interplay between hepatic and immune telomerase maintenance while highlighting the telomerase complex as a possible therapeutic target 29…”

Section: Discussionmentioning

confidence: 96%

Relationship between Telomere Maintenance and Liver Disease

2019

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Previous studies have established a correlation between increasing chronological age and risk of cirrhosis. This pattern raised interest in the role of telomeres and the telomerase complex in the pathogenesis of liver fibrosis and cirrhosis. This review aims to summarize and analyze the current understanding of telomere regulation in hepatocytes and lymphocytes and how this ultimately relates to the development of liver fibrosis. Notably, in chronic viral hepatitis, telomere shortening in hepatocytes and lymphocytes occurs in such a way that may promote further viral replication while also leading to liver damage. However, while telomere shortening occurs in both hepatocytes and lymphocytes and ultimately results in cellular death, the mechanisms of telomere loss appear to be initiated by independent processes. The understanding of telomere maintenance on a hepatic and immune system level in both viral and non-viral etiologies of cirrhosis may open doors to novel therapeutic strategies.

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“…Taking into consideration the confidence on 8-oxodG determination as a good marker of DNA damage, our findings are remarkable indicating a broad damage induced by DEN in an hypercholesterolemic environment. Even more, activation of the H2AX, another excellent marker for DNA damage in humans [ 31 ], confirms the exacerbation of the genomic damage promoted by the high cholesterol liver content and DEN treatment.…”

Section: Discussionmentioning

confidence: 99%

Cholesterol overload in the liver aggravates oxidative stress-mediated DNA damage and accelerates hepatocarcinogenesis

et al. 2017

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Primary liver cancers represent the second leading cause of cancer-related deaths worldwide. Diverse etiological factors include chronic viral hepatitis, aflatoxin and alcohol exposure as well as aberrant liver lipid overload. Cholesterol has been identified as a key inducer of metabolic impairment, oxidative stress and promoter of cellular dysfunction. The aim of this work was to address the oxidative stress-mediated DNA damage induced by cholesterol overload, and its role in the development of hepatocellular carcinoma.C57BL/6 male mice were fed with a high cholesterol diet, followed by a single dose of N-diethylnitrosamine (DEN, 10 μg/g, ip). Reactive oxygen species generation, DNA oxidation, antioxidant and DNA repair proteins were analyzed at different time points. Diet-induced cholesterol overload caused enhanced oxidative DNA damage in the liver and was associated with a decrease in key DNA repair genes as early as 7 days. Interestingly, we found a cell survival response, induced by cholesterol, judged by a decrement in Bax to Bcl2 ratio. Importantly, N-acetyl-cysteine supplementation significantly prevented DNA oxidation damage. Furthermore, at 8 months after DEN administration, tumor growth was significantly enhanced in mice under cholesterol diet in comparison to control animals. Together, these results suggest that cholesterol overload exerts an oxidative stress-mediated effects and promotes the development of liver cancer.

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Liver damage and senescence increases in patients developing hepatocellular carcinoma

Abstract: Hepatocytes from patients developing HCC go through more pronounced cell damage and senescence in contrast to cirrhotic patients remaining tumor free.

Cited by 16 publications

References 23 publications

Development Of A Three-Gene Prognostic Signature For Hepatitis B Virus Associated Hepatocellular Carcinoma Based On Integrated Transcriptomic Analysis

Development Of A Three-Gene Prognostic Signature For Hepatitis B Virus Associated Hepatocellular Carcinoma Based On Integrated Transcriptomic Analysis

Relationship between Telomere Maintenance and Liver Disease

Cholesterol overload in the liver aggravates oxidative stress-mediated DNA damage and accelerates hepatocarcinogenesis

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