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Biomedicines
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NASH as an Inducer of Hepatocellular Carcinoma (HCC)
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NASH as an Inducer of Hepatocellular Carcinoma (HCC)

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 15463

Special Issue Editors

Prof. Dr. Ronit Shiri-Sverdlov

E-Mail Website
Guest Editor
NUTRIM, Department of Molecular Genetics, Maastricht University, Maastricht, The Netherlands
Interests: translational research related to inflammation and metabolic health
Special Issues, Collections and Topics in MDPI journals
Dr. Sabine Baumgartner

E-Mail Website
Guest Editor
Department of Nutrition and Movement Sciences, Maastricht University, Maastricht, The Netherlands
Interests: nutrition; NASH; lipid metabolism
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Non-alcoholic fatty liver disease (NAFLD) can progress into non-alcoholic steato-hepatitis (NASH), which is characterised by steatosis and inflammation, and in some cases, this may also develop into fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The global increase in the prevalence of NASH has led to a drastic increase in the incident of HCC. Consequently, NASH is evolving as an increasing global health threat. NASH induced HCC (NASH-HCC) is among the deadliest cancers and the fastest growing cause of HCC in liver transplant candidates. Factors influencing NASH-HCC progression include: estrogen, fibrosis, insulin, and circadian rhythm disruption. Currently, therapeutic options for NASH-HCC are limited, and survival rates are poor.

This Special Issue supports new insights into basic and clinical research on NASH-HCC. This collection of papers will shed light on the pathophysiology, clinical problems, diagnostic methods, therapeutic approaches and lifestyle adaptations of NASH-HCC, as well as on its systemic risk factors. The overall aim of this Special Issue is to raise awareness of the opportunities and challenges in translational NASH-HCC research, i.e., to explore possible answers that basic research can provide, and vice versa, to translate basic research questions to human situations. This Special Issue invites all junior and senior researchers and clinicians in the field of HASH-HCC, to share their novel findings and new ideas.

Prof. Dr. Ronit Shiri-Sverdlov
Dr. Sabine Baumgartner
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • mouse models
  • mechanisms
  • fibrosis
  • diagnosis
  • prognosis
  • novel treatments

Related Special Issue

Published Papers (5 papers)

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Research

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0 pages, 2099 KiB  
Article
Network Analysis for the Discovery of Common Oncogenic Biomarkers in Liver Cancer Experimental Models
by Loraine Kay D. Cabral, Pablo J. Giraudi, Gianluigi Giannelli, Francesco Dituri, Roberto Negro, Claudio Tiribelli and Caecilia H. C. Sukowati
Biomedicines 2023, 11(2), 342; https://doi.org/10.3390/biomedicines11020342 - 25 Jan 2023
Cited by 1 | Viewed by 1506
Abstract
Hepatocellular carcinoma (HCC) is a malignancy marked by heterogeneity. This study aimed to discover target molecules for potential therapeutic efficacy that may encompass HCC heterogeneity. In silico analysis using published datasets identified 16 proto-oncogenes as potential pharmacological targets. We used an immortalized hepatocyte [...] Read more.
Hepatocellular carcinoma (HCC) is a malignancy marked by heterogeneity. This study aimed to discover target molecules for potential therapeutic efficacy that may encompass HCC heterogeneity. In silico analysis using published datasets identified 16 proto-oncogenes as potential pharmacological targets. We used an immortalized hepatocyte (IHH) and five HCC cell lines under two subtypes: S1/TGFβ-Wnt-activated (HLE, HLF, and JHH6) and the S2/progenitor subtype (HepG2 and Huh7). Three treatment modalities, 5 µM 5-Azacytidine, 50 µM Sorafenib, and 20 nM PD-L1 gene silencing, were evaluated in vitro. The effect of treatments on the proto-oncogene targets was assessed by gene expression and Western blot analysis. Our results showed that 10/16 targets were upregulated in HCC cells, where cells belonging to the S2/progenitor subtype had more upregulated targets compared to the S1/TGFβ-Wnt-activated subtype (81% vs. 62%, respectively). Among the targets, FGR was consistently down-regulated in the cell lines following the three different treatments. Sorafenib was effective to down-regulate targets in S2/progenitor subtype while PD-L1 silencing was able to decrease targets in all HCC subtypes, suggesting that this treatment strategy may comprise cellular heterogeneity. This study strengthens the relevance of liver cancer cellular heterogeneity in response to cancer therapies. Full article
(This article belongs to the Special Issue NASH as an Inducer of Hepatocellular Carcinoma (HCC))
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19 pages, 8992 KiB  
Article
Cisd2 Preserves the Youthful Pattern of the Liver Proteome during Natural Aging of Mice
by Chen-Hua Huang, Yi-Long Huang, Zhao-Qing Shen, Chao-Hsiung Lin and Ting-Fen Tsai
Biomedicines 2021, 9(9), 1229; https://doi.org/10.3390/biomedicines9091229 - 15 Sep 2021
Cited by 5 | Viewed by 2138
Abstract
Cisd2 (CDGSH iron sulfur domain 2) is a pro-longevity gene that extends the lifespan and health span of mice, ameliorates age-associated structural damage and limits functional decline in multiple tissues. Non-alcoholic fatty liver disease (NAFLD), which plays an important role in age-related liver [...] Read more.
Cisd2 (CDGSH iron sulfur domain 2) is a pro-longevity gene that extends the lifespan and health span of mice, ameliorates age-associated structural damage and limits functional decline in multiple tissues. Non-alcoholic fatty liver disease (NAFLD), which plays an important role in age-related liver disorders, is the most common liver disease worldwide. However, no medicines that can be used to specifically and effectively treat NAFLD are currently approved for this disease. Our aim was to provide pathological and molecular evidence to show that Cisd2 protects the liver from age-related dysregulation of lipid metabolism and protein homeostasis. This study makes four major discoveries. Firstly, a persistently high level of Cisd2 protects the liver from age-related fat accumulation. Secondly, proteomics analysis revealed that Cisd2 ameliorates age-related dysregulation of lipid metabolism, including lipid biosynthesis and β-oxidation, in mitochondria and peroxisomes. Thirdly, Cisd2 attenuates aging-associated oxidative modifications of proteins. Finally, Cisd2 regulates intracellular protein homeostasis by maintaining the functionality of molecular chaperones and protein synthesis machinery. Our proteomics findings highlight Cisd2 as a novel molecular target for the development of therapies targeting fatty liver diseases, and these new therapies are likely to help prevent subsequent malignant progression to cirrhosis and hepatocellular carcinoma. Full article
(This article belongs to the Special Issue NASH as an Inducer of Hepatocellular Carcinoma (HCC))
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Review

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19 pages, 24473 KiB  
Review
All Roads Lead to Cathepsins: The Role of Cathepsins in Non-Alcoholic Steatohepatitis-Induced Hepatocellular Carcinoma
by Hester van Mourik, Mengying Li, Sabine Baumgartner, Jan Theys and Ronit Shiri-Sverdlov
Biomedicines 2022, 10(10), 2351; https://doi.org/10.3390/biomedicines10102351 - 21 Sep 2022
Cited by 1 | Viewed by 2556
Abstract
Cathepsins are lysosomal proteases that are essential to maintain cellular physiological homeostasis and are involved in multiple processes, such as immune and energy regulation. Predominantly, cathepsins reside in the lysosomal compartment; however, they can also be secreted by cells and enter the extracellular [...] Read more.
Cathepsins are lysosomal proteases that are essential to maintain cellular physiological homeostasis and are involved in multiple processes, such as immune and energy regulation. Predominantly, cathepsins reside in the lysosomal compartment; however, they can also be secreted by cells and enter the extracellular space. Extracellular cathepsins have been linked to several pathologies, including non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). NASH is an increasingly important risk factor for the development of HCC, which is the third leading cause of cancer-related deaths and poses a great medical and economic burden. While information regarding the involvement of cathepsins in NASH-induced HCC (NASH-HCC) is limited, data to support the role of cathepsins in either NASH or HCC is accumulating. Since cathepsins play a role in both NASH and HCC, it is likely that the role of cathepsins is more significant in NASH-HCC compared to HCC derived from other etiologies. In the current review, we provide an overview on the available data regarding cathepsins in NASH and HCC, argue that cathepsins play a key role in the transition from NASH to HCC, and shed light on therapeutic options in this context. Full article
(This article belongs to the Special Issue NASH as an Inducer of Hepatocellular Carcinoma (HCC))
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27 pages, 928 KiB  
Review
Genetics, Immunity and Nutrition Boost the Switching from NASH to HCC
by Paola Dongiovanni, Marica Meroni, Miriam Longo, Silvia Fargion and Anna Ludovica Fracanzani
Biomedicines 2021, 9(11), 1524; https://doi.org/10.3390/biomedicines9111524 - 23 Oct 2021
Cited by 11 | Viewed by 2846
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the leading contributor to the global burden of chronic liver diseases. The phenotypic umbrella of NAFLD spans from simple and reversible steatosis to nonalcoholic steatohepatitis (NASH), which may worsen into cirrhosis and hepatocellular carcinoma (HCC). Notwithstanding, HCC [...] Read more.
Nonalcoholic fatty liver disease (NAFLD) is the leading contributor to the global burden of chronic liver diseases. The phenotypic umbrella of NAFLD spans from simple and reversible steatosis to nonalcoholic steatohepatitis (NASH), which may worsen into cirrhosis and hepatocellular carcinoma (HCC). Notwithstanding, HCC may develop also in the absence of advanced fibrosis, causing a delayed time in diagnosis as a consequence of the lack of HCC screening in these patients. The precise event cascade that may precipitate NASH into HCC is intricate and it entails diverse triggers, encompassing exaggerated immune response, endoplasmic reticulum (ER) and oxidative stress, organelle derangement and DNA aberrancies. All these events may be accelerated by both genetic and environmental factors. On one side, common and rare inherited variations that affect hepatic lipid remodeling, immune microenvironment and cell survival may boost the switching from steatohepatitis to liver cancer, on the other, diet-induced dysbiosis as well as nutritional and behavioral habits may furtherly precipitate tumor onset. Therefore, dietary and lifestyle interventions aimed to restore patients’ health contribute to counteract NASH progression towards HCC. Even more, the combination of therapeutic strategies with dietary advice may maximize benefits, with the pursuit to improve liver function and prolong survival. Full article
(This article belongs to the Special Issue NASH as an Inducer of Hepatocellular Carcinoma (HCC))
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14 pages, 1014 KiB  
Review
The Role of Oxidative Stress in NAFLD–NASH–HCC Transition—Focus on NADPH Oxidases
by Daniela Gabbia, Luana Cannella and Sara De Martin
Biomedicines 2021, 9(6), 687; https://doi.org/10.3390/biomedicines9060687 - 17 Jun 2021
Cited by 53 | Viewed by 5077
Abstract
A peculiar role for oxidative stress in non-alcoholic fatty liver disease (NAFLD) and its transition to the inflammatory complication non-alcoholic steatohepatitis (NASH), as well as in its threatening evolution to hepatocellular carcinoma (HCC), is supported by numerous experimental and clinical studies. NADPH oxidases [...] Read more.
A peculiar role for oxidative stress in non-alcoholic fatty liver disease (NAFLD) and its transition to the inflammatory complication non-alcoholic steatohepatitis (NASH), as well as in its threatening evolution to hepatocellular carcinoma (HCC), is supported by numerous experimental and clinical studies. NADPH oxidases (NOXs) are enzymes producing reactive oxygen species (ROS), whose abundance in liver cells is closely related to inflammation and immune responses. Here, we reviewed recent findings regarding this topic, focusing on the role of NOXs in the different stages of fatty liver disease and describing the current knowledge about their mechanisms of action. We conclude that, although there is a consensus that NOX-produced ROS are toxic in non-neoplastic conditions due to their role in the inflammatory vicious cycle sustaining the transition of NAFLD to NASH, their effect is controversial in the neoplastic transition towards HCC. In this regard, there are indications of a differential effect of NOX isoforms, since NOX1 and NOX2 play a detrimental role, whereas increased NOX4 expression appears to be correlated with better HCC prognosis in some studies. Further studies are needed to fully unravel the mechanisms of action of NOXs and their relationships with the signaling pathways modulating steatosis and liver cancer development. Full article
(This article belongs to the Special Issue NASH as an Inducer of Hepatocellular Carcinoma (HCC))
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