Elucidation of EB virus-associated epithelial tumorigenesis by integrated understanding of in vitro and in vivo studies

• Project/Area Number: 18K07148
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49060:Virology-related
• Research Institution: Shimane University
• Principal Investigator: Yoshiyama Hironori 島根大学, 学術研究院医学・看護学系, 教授 (10253147)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: Epstein-Barr virus / 上皮性腫瘍 / 上咽頭癌 / 口腔癌 / EBV / 頭頸部扁平上皮癌 / 上皮間葉転換 / ワーブルグ効果 / 口腔扁平上皮癌 / EBウイルス

Outline of Final Research Achievements

It was suspected that the accumulation of genetic abnormalities caused by DNA editing enzymes was involved in the formation of cancer cells following EMT. From this, we considered to clarify the possibility that EBV infection dedifferentiates epithelial cells and acts on the formation of cancer stem cells by combining multiple experiments.

Academic Significance and Societal Importance of the Research Achievements

Epstein-Barr virusは、9割以上の人が感染するヘルペスウイルスの一種で、潜伏持続感染細胞が増殖することでEBVの増殖が行われる。感染細胞はEBV潜伏感染遺伝子が発する増殖刺激により分裂を重ね、腫瘍を形成する。上皮性腫瘍細胞は、単一の感染細胞が腫瘍細胞の起源であるにもかかわらず、腫瘍化機構の階層的、経時的な理解は不十分である。
申請者は、薬剤選択遺伝子を持つ組換えEBVを用いて、持続感染上皮細胞株を作製し、上皮細胞が、EBVに感染すると、上皮間葉転換することに気付いた。これより、EBV感染が、上皮細胞を脱分化し癌幹細胞の形成に働く可能性を、複数の実験を組合わせて明らかにする。

Research Products

• [Int'l Joint Research] National University of Singapore(シンガポール)
• [Int'l Joint Research] Kohn Kaen University(タイ)
• [Int'l Joint Research] George Town University(米国)
• [Int'l Joint Research] Khon Kaen University(タイ)
• [Int'l Joint Research] Ningxia Medical University/Dalian University(中国)
• [Int'l Joint Research] Department of Microbiology/Faculty of Medicine/Khon Kaen University(タイ)
• [Journal Article] Role of Viral and Host microRNAs in Immune Regulation of Epstein-Barr Virus-Associated Diseases. (2020)
  • Author(s): Iizasa H, Kim H, Kartika AV, Kanehiro Y, Yoshiyama H.
  • Journal Title: Front Immunol. Volume: 11 Pages: 367-367
  • DOI: 10.3389/fimmu.2020.00367
  • Peer Reviewed / Open Access
• [Journal Article] ADAR2 Regulates Malignant Behaviour of Mesothelioma Cells Independent of RNA-editing Activity. (2020)
  • Author(s): Sakata KI, Maeda K, Sakurai N, Liang S, Nakazawa S, Yanagihara K, Kubo T, Yoshiyama H, Kitagawa Y, Hamada JI, Iizasa H.
  • Journal Title: ANTICANCER RESEARCH Volume: 40 Issue: 3 Pages: 1307-1314
  • DOI: 10.21873/anticanres.14072
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Infection-Associated Cancers (2020)
  • Author(s): Yoshiyama Hironori、Ueda Keiji、Komano Jun、Iizasa Hisashi
  • Journal Title: Journal of Oncology Volume: 2020 Pages: 1-2
  • DOI: 10.1155/2020/4979131
  • Peer Reviewed / Open Access
• [Journal Article] Epstein-Barr Virus Infection of Oral Squamous Cells. (2020)
  • Author(s): Heawchaiyaphum C, Iizasa H, Ekalaksananan T, Burassakarn A, Kiyono T, Kanehiro Y, Yoshiyama H, Pientong C.
  • Journal Title: Microorganisms Volume: 16 Issue: 3 Pages: 419-419
  • DOI: 10.3390/microorganisms8030419
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] NONO is a negative regulator for SOX2 promoter. (2020)
  • Author(s): Liang S, Takahashi H, Hirose T, Kuramitsu Y, Hatakeyama S, Yoshiyama H, Wang R, Hamada J, Iizasa H.
  • Journal Title: Cancer Genomics & Proteomics Volume: 17 Issue: 4 Pages: 359-367
  • DOI: 10.21873/cgp.20195
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Application of Biopsy Samples Used for Helicobacter pylori Urease Test to Predict Epstein?Barr Virus-Associated Cancer (2020)
  • Author(s): Kartika Andy Visi、Iizasa Hisashi、Ding Dan、Kanehiro Yuichi、Tajima Yoshitsugu、Kaji Shunsuke、Yanai Hideo、Yoshiyama Hironori
  • Journal Title: Microorganisms Volume: 8 Issue: 6 Pages: 923-923
  • DOI: 10.3390/microorganisms8060923
  • Peer Reviewed / Open Access
• [Journal Article] Epstein-Barr Virus Mediated Signaling in Nasopharyngeal Carcinoma Carcinogenesis (2020)
  • Author(s): Richardo Timmy、Prattapong Pongphol、Ngernsombat Chawalit、Wisetyaningsih Nurulfitri、Iizasa Hisashi、Yoshiyama Hironori、Janvilisri Tavan
  • Journal Title: Cancers Volume: 12 Issue: 9 Pages: 2441-2441
  • DOI: 10.3390/cancers12092441
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Epstein?Barr Virus Infection of Pseudostratified Nasopharyngeal Epithelium Disrupts Epithelial Integrity (2020)
  • Author(s): Yu Fenggang、Lu Yanan、Li Yingying、Uchio Yuji、Pangnguriseng Utomo Andi、Kartika Andy Visi、Iizasa Hisashi、Yoshiyama Hironori、Loh Kwok Seng
  • Journal Title: Cancers Volume: 12 Issue: 9 Pages: 2722-2722
  • DOI: 10.3390/cancers12092722
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A single nucleotide polymorphism in the BART promoter region of Epstein-Barr virus isolated from nasopharyngeal cancer cells (2019)
  • Author(s): Kim Hyoji、Burassakarn Ati、Kang Yuting、Iizasa Hisashi、Yoshiyama Hironori
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 520 Issue: 2 Pages: 373-378
  • DOI: 10.1016/j.bbrc.2019.10.028
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinicopathologic Characteristics of Epstein?Barr Virus-Associated Gastric Cancer Over the Past Decade in Japan (2019)
  • Author(s): Yanagi、Nishikawa、Shimokuri、Shuto、Takagi、Takagi、Kobayashi、Yamamoto、Miura、Yanai、Suehiro、Yamasaki、Yoshiyama、Sakaida
  • Journal Title: Microorganisms Volume: 7 Issue: 9 Pages: 305-305
  • DOI: 10.3390/microorganisms7090305
  • Peer Reviewed / Open Access
• [Journal Article] Adenosine deaminase acting on RNA-1 (ADAR1) inhibits hepatitis B virus (HBV) replication by enhancing microRNA-122 processing (2019)
  • Author(s): Liu Guangyan、Ma Xiancai、Wang Zhe、Wakae Kousho、Yuan Yaochang、He Zhangping、Yoshiyama Hironori、Iizasa Hisashi、Zhang Hui、Matsuda Mami、Sugiyama Ryuichi、Yuan Zhiyu、Muramatsu Masamichi、Li Linghua
  • Journal Title: Journal of Biological Chemistry Volume: 294 Issue: 38 Pages: 14043-14054
  • DOI: 10.1074/jbc.ra119.007970
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Epstein-Barr virus detection using gastric biopsy specimens after rapid urease test for Helicobacter pylori (2019)
  • Author(s): Yanai Hideo、Iizasa Hisashi、Chihara Daisuke、Murakami Tomoyuki、Nishikawa Jun、Yoshiyama Hironori
  • Journal Title: Endoscopy International Open Volume: 07 Issue: 04 Pages: E431-E432
  • DOI: 10.1055/a-0859-7233
  • Peer Reviewed / Open Access
• [Journal Article] The Role of Transforming Growth Factor β in Cell-to-Cell Contact-Mediated Epstein-Barr Virus Transmission (2018)
  • Author(s): Nanbo A, Ohashi M, Yoshiyama H, Ohba Y
  • Journal Title: Front Microbiol Volume: 9 Pages: 984-984
  • DOI: 10.3389/fmicb.2018.00984
  • NAID: 120006489803
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Importance of Epstein?Barr Virus-Associated Gastric Cancer (2018)
  • Author(s): Nishikawa Jun、Iizasa Hisashi、Yoshiyama Hironori、Shimokuri Kanami、Kobayashi Yuki、Sasaki Sho、Nakamura Munetaka、Yanai Hideo、Sakai Kohei、Suehiro Yutaka、Yamasaki Takahiro、Sakaida Isao
  • Journal Title: Cancers Volume: 10 Issue: 6 Pages: 167-167
  • DOI: 10.3390/cancers10060167
  • Peer Reviewed / Open Access
• [Journal Article] Identification of novel mycobacterial inhibitors against mycobacterial protein kinase G. (2018)
  • Author(s): Kanehiro Y, Tomioka H, Pieters J, Tatano Y, Kim H, Iizasa H, Yoshiyama H.
  • Journal Title: Frontiers in Microbiology Volume: 9 Pages: 1517-1517
  • DOI: 10.3389/fmicb.2018.01517
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Establishment of EBV latency in nasopharyngeal tumor epithelial cells by in vivo cell-mediated transfer infection (2018)
  • Author(s): Yua Fenggang、Lu Yanan、K Tay Joshua、Yoshiyam Hironori、Seng Loh Kwok
  • Journal Title: Otorhinolaryngology-Head and Neck Surgery Volume: 3 Issue: 3 Pages: 1-7
  • DOI: 10.15761/ohns.1000174
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] EBV-associated gastric cancer evades T-cell immunity by PD-1/PD-L1 interactions (2018)
  • Author(s): Sasaki Sho、Nishikawa Jun、Sakai Kohei、Iizasa Hisashi、Yoshiyama Hironori、Yanagihara Masashi、Shuto Takuya、Shimokuri Kanami、Kanda Teru、Suehiro Yutaka、Yamasaki Takahiro、Sakaida Isao
  • Journal Title: Gastric Cancer Volume: 21 Issue: 3 Pages: 486-496
  • DOI: 10.1007/s10120-018-0880-4
  • NAID: 40021884057
  • Peer Reviewed / Open Access
• [Journal Article] Regulation of Epstein-Barr Virus Life Cycle and Cell Proliferation by Histone H3K27 Methyltransferase EZH2 in Akata Cells (2018)
  • Author(s): Ichikawa Takaya、Okuno Yusuke、Sato Yoshitaka、Goshima Fumi、Yoshiyama Hironori、Kanda Teru、Kimura Hiroshi、Murata Takayuki
  • Journal Title: mSphere Volume: 3 Issue: 6
  • DOI: 10.1128/msphere.00478-18
  • Peer Reviewed / Open Access
• [Presentation] Regulation of Epstein-Barr virus encoded microRNA in epithelial tumors (2020)
  • Author(s): Hironori Yoshiyama
  • Organizer: `U.S.-Japan Cooperative Medical Sciences Program's 22nd International Conference On Emerging Infectious Diseases In The Pacific Rim’
  • Int'l Joint Research / Invited
• [Presentation] Comparison between SARS-CoV-2 and influenza virus (2020)
  • Author(s): Hironori Yoshiyama
  • Organizer: `International Webmir for 28th Anniversary of Faculty of Medicine UMI and 66th Anniversary of Universitas
  • Int'l Joint Research / Invited
• [Presentation] 上咽頭癌におけるEBウイルスのBARTプロモーター領域におけるSNPの頻繁な検出 (2020)
  • Author(s): Hisashi Iizasa, Hyoji Kim, Ati Burassakarn , Yuting Kang, Hironori Yoshiyama
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] ピロリ菌迅速ウレアーゼ試験に使用された胃内視鏡生検サンプルからのEBウイルスゲノムDNAの検出 (2020)
  • Author(s): Andy Visi Kartika, Hisashi Iizasa, Dang Ding, Sintayehu Fekadu, Yuichi Kanehiro, Shyunsuke Kaji, Hideo Yanai, Hironori Yoshiyama
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Regulation of Epstein-Barr virus encoded microRNA in epithelial tumors. (2020)
  • Author(s): Yoshiyama Hironori
  • Organizer: U.S.-Japan Cooperative Medical Sciences Program's 22nd International Conference On Emerging Infectious Diseases In The Pacific Rim
  • Int'l Joint Research / Invited
• [Presentation] Bacterial coinfection augments Epstein-Barr virus infection of gastric epithelial cells. (2019)
  • Author(s): Yoshiyama Hironori
  • Organizer: `Periodical Meeting’, Diabetes Metabolism Research Institute and the Department of Diabetes Complications, City of Hope
  • Int'l Joint Research / Invited
• [Presentation] Oncogenic properties of Epstein-Barr virus in epithelial infections. (2019)
  • Author(s): Yoshiyama Hironori
  • Organizer: `Development of Collaboration Meeting’, Indonesian Muslem University Medical Faculty
  • Int'l Joint Research / Invited
• [Presentation] Bacterial coinfection augments Epstein-Barr virus infection of gastric epithelial cells. (2019)
  • Author(s): Yoshiyama Hironori
  • Organizer: `International Medical Forum’, Ningxia Medical Faculty
  • Int'l Joint Research / Invited
• [Presentation] A single nucleotide polymorphism in the BART promoter region is characteristic of Epstein-Barr virus strain infected with nasopharyngeal cancer cells. (2019)
  • Author(s): Hisashi Iizasa, Yuting Kang, Hironori Yoshiyama
  • Organizer: 5th Rhinology Research Forum in Asia
  • Int'l Joint Research / Invited
• [Presentation] Regulation of EBV encoded BART miRNA by viral LMP 2A through host cell transcriptional activators. (2019)
  • Author(s): Kim H, Iizasa H, Kanehiro Y, Yoshiyama H
  • Organizer: The 44th Anuual International Herpesvirus Workshop
  • Int'l Joint Research
• [Presentation] Epstein-Barr virus promotes stemness of oral squamous cell carcinoma. (2019)
  • Author(s): Chukkris Heawchaiyaphum, Tipaya Ekalaksananan, Hisashi Iizasa, Yuichi Kanehiro, Tohru Kiyono, Hironori Yoshiyama, Chamsai Pientong
  • Organizer: 22nd European Society for Clinical Virology's Annual Meeting
  • Int'l Joint Research
• [Presentation] BART transcripts expressed in EBV-positive NK/T lymphoma cells regulate inflammatory cytokine expression. (2019)
  • Author(s): Hyoji Kim, Hisashi Iizasa, Yuting Kang, Norio Shimizu, Hironori Yoshiyama
  • Organizer: The 17th International Conference on Malignancies in HIV/AIDS
  • Int'l Joint Research
• [Presentation] ヘルペスウイルス感染症の重症化とウイルスの病原因子、シンポジウム３「ヘルペスウイルス感染症～重症化とその要因～」 (2018)
  • Author(s): 吉山裕規
  • Organizer: 第50回日本小児感染症学会総会
  • Invited
• [Presentation] Epstein-Barr virus infection of epithelial cells causes mitochondrial DNA mutation (2018)
  • Author(s): Kanehiro Y, Kim H, Fekadu S, Iizasa H, Yoshiyama H
  • Organizer: The 19th Royal Golden Jubilee Ph.D. Congress `Innovation Challenges toward Thailand 4.0’
  • Int'l Joint Research / Invited
• [Presentation] LMP2A regulates BART miRNAs transcription by translational activation of ETS family genes (2018)
  • Author(s): Kim H, Iizasa H, Kanehiro Y, Yoshiyama H
  • Organizer: 2018 International Conference on EBV and KSHV
  • Int'l Joint Research
• [Presentation] EBウイルスワクチン開発のための口腔咽頭癌地域集積性の研究 (2018)
  • Author(s): Chukkris Heawchaiyaphum、Sintayehu Fekadu、Amrizal Muhtar、Hyoji Kim、上野詩織、田中星奈、飯笹久、吉山裕規
  • Organizer: 平成30年度 海外学術調査フェスタ・ポスター発表
• [Presentation] Biological properties of Epstein-Barr virus positive oral squamous cell carcinoma cell lines (2018)
  • Author(s): Chukkris Heawchaiyaphum, Tipaya Ekalaksananan, Hisashi Iizasa, Yuichi Kanehiro, Tohru Kiyono, Hironori Yoshiyama, Chamsai Pientong
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Transcriptional activation of Epstein-Barr virus encoded BART miRNAs in NK/T lymphomas (2018)
  • Author(s): Hyoji Kim、飯笹久、金廣優一、清水則夫、吉山裕規
  • Organizer: 第66回日本ウイルス学会総会
• [Book] シンプル微生物学（改訂第6版） (2018)
  • Author(s): 小熊 惠二、堀田 博、若宮 伸隆
  • Total Pages: 474
  • Publisher: 南江堂
  • ISBN: 9784524254835
• [Book] 標準微生物学 第13版 (2018)
  • Author(s): 中込 治
  • Total Pages: 676
  • Publisher: 医学書院
  • ISBN: 9784260034562
• [Remarks] 島根大学医学部微生物学講座ホームページ
  • URL: http://yoshiyama-lab.org
• [Remarks] 島根大学研究・学術情報機構戦略的研究センター「健康長寿のための感染症包括ケアプロジェクトセンター」
  • URL: https://www.proken.shimane-u.ac.jp/project_center/
• [Remarks] 島根大学医学部微生物講座
  • URL: http://yoshiyama-lab.org
• [Remarks] 島根大学医学部微生物学講座
  • URL: https://yoshiyama-lab.org/en/