Establishment of MCPyV-infection experimental system and the therapy base on the carcinogenesis of MCPyV-positive Merkel cell carcinoma

• Project/Area Number: 17K08720
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Tottori University
• Principal Investigator: HAYASHI Kazuhiko 鳥取大学, 医学部, 特任教員 (30180962)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: メルケル細胞癌 / メルケル細胞ポリオーマウイルス / シグナル伝達系 / 腫瘍微小環境 / エピジェネティクス / ヒストンH3K27me3 / Mismatch Repair (MMR) / NOTCHシグナル伝達経路 / トリプトファン代謝経路 / ランゲルハンス組織球症 / ポリオーマウイルス / 病理学

Outline of Final Research Achievements

Approximately 80% of Merkel cell carcinoma(MCC), an aggressive skin neuroendocrine carcinoma, are infected with polyomavirus (MCPyV). We reported several significant findings on Notch signaling, epigenetics, Try metabolism and DNA mismatch repair etc. in the different carcinogenesis between MCPyV(+)MCC and MCPyV(-)MCC, which are useful for development of new therapy.
We have failed to establish the in vitro culture system of MCPyV-producing cell, which is a basic method to study the biology of MCPyV.

Academic Significance and Societal Importance of the Research Achievements

メルケル細胞癌(MCC)は高悪性度の皮膚神経内分泌癌であり、その約80％がウイルス(MCPyV)に感染している。予後不良に関与する発癌機序もMCPyV(+)MCCとMCPyV(-)MCCで異なるため、これらの分子生物学的異常（Notchシグナル、ヒストン、トリプトファン代謝系、ミスマッチ修復等）の違いを明らかにしたことは、MCPyV(+)MCCとMCPyV(-)MCCとで別々に有効な治療法開発のために有用な情報基盤となる。
MCPyVの生物学的特性を明らかにする基礎的研究基盤となるウイルス産生系培養細胞株樹立による実験系確立を試みたが不成功だった。

Research Products

• [Int'l Joint Research] Department of Cellular Pathology,/Guy's and St Thomas' NHS Foundation/University of Manchester(英国)
• [Int'l Joint Research] Department of Cellular Pathology,/Guy's and St Thomas' NHS Foundation/University of Manchester(英国)
• [Int'l Joint Research] Department of Pathology/Christie NHS Foundation Trust/Manchester, M20 4BX(United Kingdom)
• [Journal Article] Expression of Notch 3 and Jagged 1 Is Associated With Merkel Cell Polyomavirus Status and Prognosis in Merkel Cell Carcinoma. (2019)
  • Author(s): Wardhani LO, Matsushita M, Kuwamoto S, Nonaka D, Nagata K, Kato M, Kitamura Y, Hayashi K
  • Journal Title: Anticancer Research Volume: 39 Issue: 1 Pages: 319-329
  • DOI: 10.21873/anticanres.13114
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Decreased H3K27me3 Expression is Associated With Merkel Cell Polyomavirus-Negative Merkel Cell Carcinoma, Especially Combined With Cutaneous Squamous Cell Carcinoma (2019)
  • Author(s): Michiko Matsushita, Takeshi Iwasaki, Lusi Oka Wardhani, Satoshi Kuwamoto, Daisuke Nonaka, Keiko Nagata, Masako Kato , Yukisato Kitamura , Kazuhiko Hayashi
  • Journal Title: Anticancer Res. Volume: 39 Issue: 10 Pages: 5573-5579
  • DOI: 10.21873/anticanres.13751
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Expression of the IDO1/TDO2-AhR pathway in tumor cells or the tumor microenvironment is associated with MCPyV status and prognosis in Merkel cell carcinoma (2019)
  • Author(s): Lusi Oka Wardhani, Michiko Matsushita, Takeshi Iwasaki, Satoshi Kuwamoto, Daisuke Nonaka, , Keiko Nagat, Masako Kato, Yukisato Kitamura, Kazuhiko Hayashi
  • Journal Title: Hum Pathol Volume: 84 Pages: 52-61
  • DOI: 10.1016/j.humpath.2018.09.003
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Merkel cell polyomavirus and Langerhans cell neoplasm. (2018)
  • Author(s): Murakami I, Wada N, Nakashima J, Iguchi M, Toi M, Hashida Y, Higuchi T, Daibata M, Matsushita M, Iwasaki T, Kuwamoto S, Horie Y, Nagata K, Hayashi K, Oka T, Yoshino T, Imamura T, Morimoto A, Imashuku S, Gogusev J, Jaubert F.
  • Journal Title: Cell Commun Signal. Volume: 16(1) Issue: 1 Pages: 49-49
  • DOI: 10.1186/s12964-018-0261-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 感染性疾患の病理、Merkel細胞癌とMerkel細胞ポリオーマウイルス (2018)
  • Author(s): 桑本 聡史、松下倫子、林 一彦
  • Journal Title: 病理と臨床 Volume: 36 Pages: 179-185
  • Peer Reviewed
• [Journal Article] Association of expression of the hedgehog signal with Merkel cell polyomavirus infection and prognosis of Merkel cell carcinoma. (2017)
  • Author(s): Kuromi T, Matsushita M, Iwasaki T, Nonaka D, Kuwamoto S, Nagata K, Kato M, Akizuki G, Kitamura Y, Hayashi K
  • Journal Title: Hum Pathol Volume: 69:8-14 Pages: 8-14
  • DOI: 10.1016/j.humpath.2017.05.011
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Higher Expression of Activation-induced Cytidine Deaminase Is Significantly Associated with Merkel Cell Polyomavirus-negative Merkel Cell Carcinomas. (2017)
  • Author(s): Matsushita M, Iwasaki T, Nonaka D, Kuwamoto S, Nagata K, Kato M, Kitamura Y, Hayashi K
  • Journal Title: Yonago Acta Med Volume: 60(3): Pages: 145-153
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Epstein-Barr Virus Lytic Reactivation Activates B Cells Polyclonally and Induces Activation-Induced Cytidine Deaminase Expression: A Mechanism Underlying Autoimmunity and Its Contribution to Graves' Disease (2017)
  • Author(s): Nagata, K. Kumata, K. Nakayama, Y. Satoh, Y. Sugihara, H. Hara, S. Matsushita, M. Kuwamoto, S. Kato, M. Murakami, I. Hayashi, K.
  • Journal Title: Viral Immunol Volume: 30 Issue: 3 Pages: 240-249
  • DOI: 10.1089/vim.2016.0179
  • Peer Reviewed / Open Access
• [Journal Article] Aberrant expression of AID and AID activators of NF-κB and PAX5 is irrelevant to EBV-associated gastric cancers, but is associated with carcinogenesis in certain EBV-non-associated gastric cancers. (2017)
  • Author(s): Mohri T, Nagata K, Kuwamoto S, Matsushita M, Sugihara H, Kato M, Horie Y, Murakami I, Hayashi K.
  • Journal Title: Oncol Lett. Volume: 13 (6) Issue: 6 Pages: 4133-4140
  • DOI: 10.3892/ol.2017.5978
  • Peer Reviewed / Open Access
• [Presentation] The expression of Notch signaling pathway in Merkel cell carcinoma (2019)
  • Author(s): Michiko Matsushita, Lusi Oka Wardhani, Takeshi Iwasaki, Satoshi Kuwamoto, Daisuke Nonaka, Keiko Nagata, Masako Kato, Yukisato Kitamura, Kazuhiko Hayashi
  • Organizer: 31st European Congress of Pathology, Nice, France
  • Int'l Joint Research
• [Presentation] Association of mismatch repair proteins with Merkel cell polyomavirus status and prognosis in Merkel cell carcinoma (2019)
  • Author(s): Lusi Oka Wardhani, Michiko Matsushita, Takeshi Iwasaki, Satoshi Kuwamoto, Daisuke Nonaka, Keiko Nagata, Masako Kato, Yukisato Kitamura, Kazuhiko Hayashi
  • Organizer: 31st European Congress of Pathology, Nice, France
  • Int'l Joint Research
• [Presentation] メルケル細胞癌の腫瘍細胞と腫瘍微小環境におけるIDO1/TDO2-AhR経路の発現 は予後と相関する (2019)
  • Author(s): 松下倫子、ルシ オカ ワードダーニ、岩崎健、桑本聡史、野中大輔、長田佳子、加藤雅子、北村幸郷、林一彦
  • Organizer: 第108回日本病理学会総会、東京
• [Presentation] The histone modification H3K27me3 is reduced in MCPyV-negative Merkel cell carcinomas. (2018)
  • Author(s): Matsushita M, Iwasaki T, Kuwamoto S, Lusi Oka Wardhani, Nonaka D, Nagata K, Kato M, Kitamura Y, Hayashi K.
  • Organizer: 30th European Congress of Pathology, Bilbao, Spain, 2018
  • Int'l Joint Research
• [Presentation] The expressions of IDO1 and TDO2 in tumor cells and their tumor microenvironment are associated with MCPyV status and prognosis in Merkel Cell Carcinomas (2018)
  • Author(s): Lusi Oka Wardhani, Matsushita M, Iwasaki T, Kuwamoto S, Nonaka D, Nagata K, Kato M, Kitamura Y, Hayashi K.
  • Organizer: 30th European Congress of Pathology, Bilbao, Spain, 2018
  • Int'l Joint Research
• [Presentation] メルケル細胞ポリオーマウイルス陰性のメルケル細胞癌では、ヒストンH3K27me3修飾が低下する (2018)
  • Author(s): 松下倫子、岩崎健、桑本聡史、野中大輔、長田佳子、加藤雅子、北村幸郷、林一彦
  • Organizer: 第107回日本病理学会総会、札幌、2018
• [Presentation] Association of Hedgehog signal expression with MCPyV infection and outcome in Merkel cell carcinoma. (2017)
  • Author(s): Matsushita M, Kuromi T, Iwasaki T, Kuwamoto S, Nonaka D, Nagata K, Kato M, Kitamura Y, Hayashi K
  • Organizer: 29th European Congress of Pathology, Amsterdam, Netherlands, 2017
  • Int'l Joint Research
• [Presentation] Altered expression of SWI/SNF complex and its significance in Merkel cell carcinoma. (2017)
  • Author(s): Matsushita M, Kuwamoto S, Iwasaki T, Nonaka D, Nagata K, Kato M, Kitamura Y, Hayashi K
  • Organizer: 29th European Congress of Pathology, Amsterdam, Netherlands, 2017
  • Int'l Joint Research
• [Presentation] Expression of NEAT1 is significantly higher in MCPyV-positive MCC than MCPyV-negative one. (2017)
  • Author(s): 秋月源、今村亮俊、山田俊理、水谷玲菜、松下倫子、長田佳子、桑本聡史、加藤雅子、秋光信佳、林一彦
  • Organizer: 第106回日本病理学会総会、東京、2017
• [Presentation] メルケル細胞癌におけるSWI/SNF複合体の発現異常とその意義に関する検討 (2017)
  • Author(s): 松下倫子、桑本聡史、岩崎健、野中大輔、長田佳子、加藤雅子、村上一郎、 北村幸郷、林一彦
  • Organizer: 第106回日本病理学会総会、東京、2017