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Cancers
Special Issues
Molecular Pathogenesis of Epstein-Barr Virus-Associated Malignancy
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Molecular Pathogenesis of Epstein-Barr Virus-Associated Malignancy

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Infectious Agents and Cancer".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 15207

Special Issue Editors

Prof. Dr. Hironori Yoshiyama

E-Mail Website
Guest Editor
Department of Microbiology, Shimane University Faculty of Medicine, Shimane 693-8501, Japan
Interests: microbial pathogenesis (HIV, EBV, H. pylori); infection associated cancers
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Asuka Nanbo

E-Mail Website
Guest Editor
National Research Center for the Control and Prevention of Infectious Diseases, Nagasaki University, Nagasaki 852-8523, Japan
Interests: virology (EBV, Ebola virus); host-virus interaction; exosome; microRNA; viral entry; viral particle formation
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Tomoharu Yasuda

E-Mail Website
Guest Editor
Department of Immunology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
Interests: immunology; B cell lymphoma; cancer and immunity

Special Issue Information

Dear Colleagues,

The propagation of Epstein–Barr virus (EBV) is strongly controlled by cell-mediated immunity in infected individuals. Therefore, EBV increases viral offspring by promoting the proliferation of persistently infected cells containing viral genomes, and EBV-associated malignancies are developed from B lymphocytes, T lymphocytes, NK cells, epithelial cells, etc. that can be infected with EBV. However, although nearly 90% of the world’s humans are infected with EBV, tumors develop only in a restricted population, and many of the oncogenic mechanisms of EBV infection are still unknown.

This Special Issue of Cancers commemorates the 19th International Symposium on Epstein–Barr Virus and associated diseases scheduled for July 2021 in Japan. However, we also welcome submissions from researchers who have not attended the conference. Submission of original research articles from basic medicine to clinical medicine including a wide range of findings from disease mechanisms to diagnosis, treatment, and prevention related to EBV-related malignant diseases is highly expected. We also welcome review articles with the author’s ideas and originality that are of interest to many readers.


Prof. Dr. Hironori Yoshiyama
Prof. Dr. Asuka Nanbo
Prof. Dr. Tomoharu Yasuda
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. Cancers is an international peer-reviewed open access semimonthly 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 2900 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

  • oncogenesis
  • heterogeneity
  • molecular mechanism
  • immunology
  • biology
  • therapy
  • prognosis
  • diagnosis
  • vaccine

Published Papers (6 papers)

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Editorial

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3 pages, 177 KiB  
Editorial
How Should We Deal with Neoplastic Disease and Serious Infections Caused by Epstein–Barr Virus?
by Hironori Yoshiyama, Asuka Nanbo and Tomoharu Yasuda
Cancers 2023, 15(11), 2889; https://doi.org/10.3390/cancers15112889 - 24 May 2023
Viewed by 752
Abstract
Epstein–Barr virus (EBV) is a ubiquitous herpesvirus, but also the first discovered human tumor virus [...] Full article
(This article belongs to the Special Issue Molecular Pathogenesis of Epstein-Barr Virus-Associated Malignancy)

Research

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15 pages, 2755 KiB  
Article
Concomitant Cytotoxic Effector Differentiation of CD4+ and CD8+ T Cells in Response to EBV-Infected B Cells
by Yumi Tamura, Keita Yamane, Yohei Kawano, Lars Bullinger, Tristan Wirtz, Timm Weber, Sandrine Sander, Shun Ohki, Yasuo Kitajima, Satoshi Okada, Klaus Rajewsky and Tomoharu Yasuda
Cancers 2022, 14(17), 4118; https://doi.org/10.3390/cancers14174118 - 25 Aug 2022
Cited by 4 | Viewed by 2264
Abstract
Most people infected by EBV acquire specific immunity, which then controls latent infection throughout their life. Immune surveillance of EBV-infected cells by cytotoxic CD4+ T cells has been recognized; however, the molecular mechanism of generating cytotoxic effector T cells of the CD4 [...] Read more.
Most people infected by EBV acquire specific immunity, which then controls latent infection throughout their life. Immune surveillance of EBV-infected cells by cytotoxic CD4+ T cells has been recognized; however, the molecular mechanism of generating cytotoxic effector T cells of the CD4+ subset remains poorly understood. Here we compared phenotypic features and the transcriptome of EBV-specific effector-memory CD4+ T cells and CD8+ T cells in mice and found that both T cell types show cytotoxicity and, to our surprise, widely similar gene expression patterns relating to cytotoxicity. Similar to cytotoxic CD8+ T cells, EBV-specific cytotoxic CD4+ T cells from human peripheral blood expressed T-bet, Granzyme B, and Perforin and upregulated the degranulation marker, CD107a, immediately after restimulation. Furthermore, T-bet expression in cytotoxic CD4+ T cells was highly correlated with Granzyme B and Perforin expression at the protein level. Thus, differentiation of EBV-specific cytotoxic CD4+ T cells is possibly controlled by mechanisms shared by cytotoxic CD8+ T cells. T-bet-mediated transcriptional regulation may explain the similarity of cytotoxic effector differentiation between CD4+ T cells and CD8+ T cells, implicating that this differentiation pathway may be directed by environmental input rather than T cell subset. Full article
(This article belongs to the Special Issue Molecular Pathogenesis of Epstein-Barr Virus-Associated Malignancy)
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16 pages, 4335 KiB  
Article
General Features and Novel Gene Signatures That Identify Epstein-Barr Virus-Associated Epithelial Cancers
by Chukkris Heawchaiyaphum, Chamsai Pientong, Hironori Yoshiyama, Hisashi Iizasa, Watcharapong Panthong and Tipaya Ekalaksananan
Cancers 2022, 14(1), 31; https://doi.org/10.3390/cancers14010031 - 22 Dec 2021
Cited by 4 | Viewed by 3255
Abstract
Epstein-Barr virus (EBV) is associated with various types of human malignancies, including nasopharyngeal carcinoma (NPC), EBV-associated gastric carcinoma (EBVaGC), and oral squamous cell carcinoma (OSCC). The present study aimed to identify gene signatures and common signaling pathways that can be used to predict [...] Read more.
Epstein-Barr virus (EBV) is associated with various types of human malignancies, including nasopharyngeal carcinoma (NPC), EBV-associated gastric carcinoma (EBVaGC), and oral squamous cell carcinoma (OSCC). The present study aimed to identify gene signatures and common signaling pathways that can be used to predict the prognosis of EBV-associated epithelial cancers (EBVaCAs) by performing an integrated bioinformatics analysis of cell lines and tumor tissues. We identified 12 differentially expressed genes (DEGs) in the EBVaCA cell lines. Among them, only four DEGs, including BAMBI, SLC26A9, SGPP2, and TMC8, were significantly upregulated. However, SLC26A9 and TMC8, but not BAMBI and SGPP2, were significantly upregulated in EBV-positive tumor tissues compared to EBV-negative tumor tissues. Next, we identified IL6/JAK/STAT3 and TNF-α/NF-κB signaling pathways as common hallmarks of EBVaCAs. The expression of key genes related to the two hallmarks was upregulated in both EBV-infected cell lines and EBV-positive tumor tissues. These results suggest that SLC26A9 and TMC8 might be gene signatures that can effectively predict the prognosis of EBVaCAs and provide new insights into the molecular mechanisms of EBV-driven epithelial cancers. Full article
(This article belongs to the Special Issue Molecular Pathogenesis of Epstein-Barr Virus-Associated Malignancy)
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13 pages, 7676 KiB  
Article
Interferon-γ Produced by EBV-Positive Neoplastic NK-Cells Induces Differentiation into Macrophages and Procoagulant Activity of Monocytes, Which Leads to HLH
by Mayumi Yoshimori, Miwako Nishio, Ayaka Ohashi, Megumi Tateishi, Ayaka Mimura, Naomi Wada, Minori Saito, Norio Shimizu, Ken-Ichi Imadome and Ayako Arai
Cancers 2021, 13(20), 5097; https://doi.org/10.3390/cancers13205097 - 12 Oct 2021
Cited by 4 | Viewed by 2797
Abstract
Epstein–Barr virus (EBV)-positive T- or NK-cell neoplasms show progressive systemic inflammation and abnormal blood coagulation causing hemophagocytic lymphohistiocytosis (HLH). It was reported that inflammatory cytokines were produced and secreted by EBV-positive neoplastic T- or NK-cells. These cytokines can induce the differentiation of monocytes [...] Read more.
Epstein–Barr virus (EBV)-positive T- or NK-cell neoplasms show progressive systemic inflammation and abnormal blood coagulation causing hemophagocytic lymphohistiocytosis (HLH). It was reported that inflammatory cytokines were produced and secreted by EBV-positive neoplastic T- or NK-cells. These cytokines can induce the differentiation of monocytes into macrophages leading to HLH. To clarify which products of EBV-positive neoplastic T- or NK-cells have effects on monocytes, we performed a co-culture assay of monocytes with the supernatants of EBV-positive T- or NK-cell lines. The expression of differentiation markers, the phagocytosis ability, and the mRNA expression of the inflammatory cytokines of THP-1, a monocytic cell line, clearly increased after culturing with the supernatants from EBV-NK-cell lines. Co-culturing with the supernatants promoted the expression of CD80 and CD206 as well as M1 and M2 macrophage markers in human monocytes. Co-culturing with the supernatants of EBV-NK-cell lines significantly enhanced the procoagulant activity and the tissue factor expression of monocytes. Interferon (IFN)-γ was elevated extremely not only in the supernatant of EBV-NK-cell lines but also in the plasma of EBV-positive NK-cell neoplasms patients accompanying HLH. Finally, we confirmed that IFN-γ directly enhanced the differentiation into M1-like macrophages and the procoagulant activity of monocytes. Our findings suggest that IFN-γ may potentially serve as a therapeutic target to regulate HLH in EBV-positive NK-cell neoplasms. Full article
(This article belongs to the Special Issue Molecular Pathogenesis of Epstein-Barr Virus-Associated Malignancy)
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Review

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16 pages, 1484 KiB  
Review
Protein Farnesylation on Nasopharyngeal Carcinoma, Molecular Background and Its Potential as a Therapeutic Target
by Eiji Kobayashi, Satoru Kondo, Hirotomo Dochi, Makiko Moriyama-Kita, Nobuyuki Hirai, Takeshi Komori, Takayoshi Ueno, Yosuke Nakanishi, Miyako Hatano, Kazuhira Endo, Hisashi Sugimoto, Naohiro Wakisaka and Tomokazu Yoshizaki
Cancers 2022, 14(12), 2826; https://doi.org/10.3390/cancers14122826 - 8 Jun 2022
Cited by 3 | Viewed by 2705
Abstract
Nasopharyngeal carcinoma (NPC) is one of the Epstein–Barr virus (EBV)-associated malignancies. NPC is highly metastatic compared to other head and neck carcinomas, and evidence has shown that the metastatic features of NPC are involved in EBV infection. The prognosis of advanced cases, especially [...] Read more.
Nasopharyngeal carcinoma (NPC) is one of the Epstein–Barr virus (EBV)-associated malignancies. NPC is highly metastatic compared to other head and neck carcinomas, and evidence has shown that the metastatic features of NPC are involved in EBV infection. The prognosis of advanced cases, especially those with distant metastasis, is still poor despite advancements in molecular research and its application to clinical settings. Thus, further advancement in basic and clinical research that may lead to novel therapeutic modalities is needed. Farnesylation is a lipid modification in the C-terminus of proteins. It enables proteins to attach to the lipid bilayer structure of cellular membranes. Farnesylation was initially identified as a key process of membrane association and activation of the RAS oncoprotein. Farnesylation is thus expected to be an ideal therapeutic target in anti-RAS therapy. Additionally, more and more molecular evidence has been reported, showing that proteins other than RAS are also farnesylated and have significant roles in cancer progression. However, although several clinical trials have been conducted in cancers with high rates of ras gene mutation, such as pancreatic carcinomas, the results were less favorable than anticipated. In contrast, favorable outcomes were reported in the results of a phase II trial on head and neck carcinoma. In this review, we provide an overview of the molecular pathogenesis of NPC in terms of the process of farnesylation and discuss the potential of anti-farnesylation therapy in the treatment of NPC. Full article
(This article belongs to the Special Issue Molecular Pathogenesis of Epstein-Barr Virus-Associated Malignancy)
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Other

9 pages, 6064 KiB  
Conference Report
19th International Symposium on Epstein–Barr Virus and Associated Diseases, 29–30 July 2021, Asahikawa, Japan
by Takumi Kumai, Miki Takahara and Yasuaki Harabuchi
Cancers 2022, 14(12), 2924; https://doi.org/10.3390/cancers14122924 - 14 Jun 2022
Cited by 1 | Viewed by 1636
Abstract
Novel insights into Epstein–Barr virus (EBV) pathogenicity were presented at the “19th International Symposium on Epstein-Barr Virus and Associated Diseases” in Asahikawa, Japan. In addition, basic and translational findings on EBV-associated tumors, including natural killer (NK)/T-cell lymphoma, gastric cancer, and nasopharyngeal cancer, were [...] Read more.
Novel insights into Epstein–Barr virus (EBV) pathogenicity were presented at the “19th International Symposium on Epstein-Barr Virus and Associated Diseases” in Asahikawa, Japan. In addition, basic and translational findings on EBV-associated tumors, including natural killer (NK)/T-cell lymphoma, gastric cancer, and nasopharyngeal cancer, were presented by an international group of scientists and clinicians. Full article
(This article belongs to the Special Issue Molecular Pathogenesis of Epstein-Barr Virus-Associated Malignancy)
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