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Special Issue "Liver Cancer: Molecular Mechanisms and Targeted Therapies"

A special issue of Medicina (ISSN 1010-660X).

Deadline for manuscript submissions: 31 October 2019.

Special Issue Editor

Guest Editor
Prof. Dr. Diego F. Calvisi

Professor of Experimental Tumor Pathology, Institut für Pathologie, Universitätsklinikum, Regensburg, Germany;
Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy
Website | E-Mail
Interests: liver cancer; hepatocellular carcinoma; cholangiocarcinoma; hepatoblastoma; mouse models; cancer genetics and epigenetics; signal transduction; cancer metabolism; precision medicine

Special Issue Information

Dear Colleagues,

Primary liver cancer (PLC) is a highly frequent and lethal tumor globally, with limited therapeutic options. Although surgical resection and liver transplantation represent effective and potentially curative treatments in the early stages of the disease, the therapeutic options for advanced PLC remain unsatisfactory to date. The only two drugs approved for the treatment of advanced hepatocellular carcinoma (HCC) are the multikinase inhibitors Sorafenib and Regorafenib, yet being associated with limited benefits to the patients in terms of patients’ overall survival. Thus, the treatment of PLC represent a major health concern worldwide.

Despite a growing number of studies on the genetic and epigenetic events associated with PLC development and progression, the understanding of the same phenomena and their functional interplay remain poorly understood. Consequently, the molecular pathogenesis of this deadly disease remains poorly characterized. Therefore, a better understanding of the available data, as well as a further investigation of the molecular mechanisms responsible for human PLC, is imperative in order to significantly improve its prevention, detection, and therapy.

Given the importance of PLC in the field of medicine and research, the journal Medicina is launching this Special Issue.

We encourage you and your co-workers to submit your articles reporting on this topic. Reviews or original articles dealing with the biochemical and molecular aspects associated with PLC pathogenesis in experimental models and humans, as well as articles providing an up-to-date overview of the use of circulating/tissue biomarkers in early diagnosis and management, are particularly welcome. In addition, we warmly invite you to submit articles reporting on evidence and expectations from innovative molecular therapeutics, with special focus on individualized approaches.

Prof. Dr. Diego Francesco Calvisi
Guest Editor

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 papers will be 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. Medicina 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 1500 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

  • Primary liver cancer
  • Hepatocellular carcinoma
  • Cholangiocarcinoma
  • Hepatoblastoma
  • Signaling pathways
  • Epigenetics
  • Experimental models
  • Biomarkers
  • Targeted therapies
  • Precision medicine

Published Papers (3 papers)

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Research

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Open AccessArticle
The Novel Nature Microtubule Inhibitor Ivalin Induces G2/M Arrest and Apoptosis in Human Hepatocellular Carcinoma SMMC-7721 Cells In Vitro
Medicina 2019, 55(8), 470; https://doi.org/10.3390/medicina55080470
Received: 30 June 2019 / Revised: 2 August 2019 / Accepted: 8 August 2019 / Published: 12 August 2019
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Abstract
Background and Objectives: Microtubules are an attractive target for cancer chemotherapy. Previously, we reported that Ivalin exhibited excellent anti-migration and anti-invasion activities in human breast cancer cells. Here, we examined the microtubule inhibition effect of Ivalin in human hepatocellular carcinoma SMMC-7721 cells. [...] Read more.
Background and Objectives: Microtubules are an attractive target for cancer chemotherapy. Previously, we reported that Ivalin exhibited excellent anti-migration and anti-invasion activities in human breast cancer cells. Here, we examined the microtubule inhibition effect of Ivalin in human hepatocellular carcinoma SMMC-7721 cells. Materials and Methods: We used the 3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium bromide (MTT) assay to evaluate the cell proliferation effect of Ivalin and flow cytometry analysis to detect the apoptotic and cell cycle arrest effects of Ivalin. Immunofluorescence staining was used to measure the effect of Ivalin on the cytoskeleton network, and Western blotting was used to detect the expression levels of Bax, Bcl-2, Cdc2, phosphor-Cdc2, Cdc25A, Cyclin B1, and tubulin. Results: Ivalin induced cell cycle G2/M arrest and subsequent triggered apoptosis in human hepatocellular carcinoma SMMC-7721 cells. Furthermore, microtubules were shown to be involved in Ivalin-meditated apoptosis. In this connection, Ivalin treatment suppressed cellular microtubule network formation by regulating microtubule depolymerization. Moreover, Western blotting revealed Cdc25A and Cyclin B1 were upregulated in Ivalin-meditated cell cycle arrest. Subsequently, the induction of Bax (a proapoptotic protein) and reduction of Bcl-2 (an anti-apoptotic protein) expression were observed in Ivalin-treated SMMC-7721 cells. Conclusion: Ivalin induced microtubule depolymerization, then blocked cells in mitotic phase, and eventually resulted in apoptosis in SMMC-7721 cells. Collectively, these data indicate that Ivalin, acting as a novel inhibitor of microtubules, could be considered as a promising lead in anticancer drug development. Full article
(This article belongs to the Special Issue Liver Cancer: Molecular Mechanisms and Targeted Therapies)
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Review

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Open AccessReview
Alterations of Methionine Metabolism as Potential Targets for the Prevention and Therapy of Hepatocellular Carcinoma
Medicina 2019, 55(6), 296; https://doi.org/10.3390/medicina55060296
Received: 20 March 2019 / Revised: 28 May 2019 / Accepted: 29 May 2019 / Published: 21 June 2019
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Abstract
Several researchers have analyzed the alterations of the methionine cycle associated with liver disease to clarify the pathogenesis of human hepatocellular carcinoma (HCC) and improve the preventive and the therapeutic approaches to this tumor. Different alterations of the methionine cycle leading to a [...] Read more.
Several researchers have analyzed the alterations of the methionine cycle associated with liver disease to clarify the pathogenesis of human hepatocellular carcinoma (HCC) and improve the preventive and the therapeutic approaches to this tumor. Different alterations of the methionine cycle leading to a decrease of S-adenosylmethionine (SAM) occur in hepatitis, liver steatosis, liver cirrhosis, and HCC. The reproduction of these changes in MAT1A-KO mice, prone to develop hepatitis and HCC, demonstrates the pathogenetic role of MAT1A gene under-regulation associated with up-regulation of the MAT2A gene (MAT1A:MAT2A switch), encoding the SAM synthesizing enzymes, methyladenosyltransferase I/III (MATI/III) and methyladenosyltransferase II (MATII), respectively. This leads to a rise of MATII, inhibited by the reaction product, with a consequent decrease of SAM synthesis. Attempts to increase the SAM pool by injecting exogenous SAM have beneficial effects in experimental alcoholic and non-alcoholic steatohepatitis and hepatocarcinogenesis. Mechanisms involved in hepatocarcinogenesis inhibition by SAM include: (1) antioxidative effects due to inhibition of nitric oxide (NO•) production, a rise in reduced glutathione (GSH) synthesis, stabilization of the DNA repair protein Apurinic/Apyrimidinic Endonuclease 1 (APEX1); (2) inhibition of c-myc, H-ras, and K-ras expression, prevention of NF-kB activation, and induction of overexpression of the oncosuppressor PP2A gene; (3) an increase in expression of the ERK inhibitor DUSP1; (4) inhibition of PI3K/AKT expression and down-regulation of C/EBPα and UCA1 gene transcripts; (5) blocking LKB1/AMPK activation; (6) DNA and protein methylation. Different clinical trials have documented curative effects of SAM in alcoholic liver disease. Furthermore, SAM enhances the IFN-α antiviral activity and protects against hepatic ischemia-reperfusion injury during hepatectomy in HCC patients with chronic hepatitis B virus (HBV) infection. However, although SAM prevents experimental tumors, it is not curative against already established experimental and human HCCs. The recent observation that the inhibition of MAT2A and MAT2B expression by miRNAs leads to a rise of endogenous SAM and strong inhibition of cancer cell growth could open new perspectives to the treatment of HCC. Full article
(This article belongs to the Special Issue Liver Cancer: Molecular Mechanisms and Targeted Therapies)
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Open AccessReview
Targeted Therapies in Cholangiocarcinoma: Emerging Evidence from Clinical Trials
Received: 15 December 2018 / Revised: 28 January 2019 / Accepted: 1 February 2019 / Published: 8 February 2019
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Abstract
Cholangiocarcinoma (CCA) is a highly-aggressive malignancy arising from the biliary tree, characterized by a steady increase in incidence globally and a high mortality rate. Most CCAs are diagnosed in the advanced and metastatic phases of the disease, due to the paucity of signs [...] Read more.
Cholangiocarcinoma (CCA) is a highly-aggressive malignancy arising from the biliary tree, characterized by a steady increase in incidence globally and a high mortality rate. Most CCAs are diagnosed in the advanced and metastatic phases of the disease, due to the paucity of signs and symptoms in the early stages. This fact, along with the poor results of the local and systemic therapies currently employed, is responsible for the poor outcome of CCA patients and strongly supports the need for novel therapeutic agents and strategies. In recent years, the introduction of next-generation sequencing technologies has opened new horizons for a better understanding of the genetic pathophysiology of CCA and, consequently, for the identification and evaluation of new treatments tailored to the molecular features or alterations progressively elucidated. In this review article, we describe the potential targets under investigation and the current molecular therapies employed in biliary tract cancers. In addition, we summarize the main drugs against CCA under evaluation in ongoing trials and describe the preliminary data coming from these pioneering studies. Full article
(This article belongs to the Special Issue Liver Cancer: Molecular Mechanisms and Targeted Therapies)
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