Analysis on the differences of tumorigenesis between MCPyV-positive and -negative Merkel cell carcinomas and its application to therapy

• Project/Area Number: 26460433
• 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, 教授 (30180962)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: メルケル細胞癌 / ポリオーマウイルス / がん遺伝子 / 遺伝子変異 / 接着因子 / 予後 / 口腔腫瘍 / 顎骨腫瘍 / 増殖マーカー / CK20陰性 / 免疫グロブリン / 新規ウイルス検出法 / シグナル伝達系

Outline of Final Research Achievements

Different mechanism of carcinogenesis between MCPyV-positive and -negative Merkel cell carcinoma (MCC) is suggested because expressions of Akt/mTOR/4E-BP1 Pathway Signals or CADM1 and MAL were associated with MCPyV infection or prognosis, and immunoglobulin expression was observed only in MCPyV-positive MCC. MCPyV-DNA was frequently detected in Langerhans cell histiocytosis or Langerhans cell sarcoma.A new in situ hybridization and immunohistochemistry with a novel antibody to detect small T-antigen expressions ofMCPyV was developed.
Phylogeny of MCPyV genomes obtained from Japanese MCPyV-infected MCCs revealed that MCPyV strains in Japanese MCCs are distinct from Caucasian type MCPyVs.

Research Products

• [Int'l Joint Research] Department of Histopathology,/the Christie NHS Foundation Trust,/Manchester(United Kingdom)
• [Int'l Joint Research] Department of Histopathology/The Christie NHS Foundation Trust/Wilmslow Road, Manchester(United Kingdom)
• [Journal Article] Comment on 'Cytokeratin 20-negative Merkel cell carcinoma is infrequently associated with the Merkel cell polyomavirus'. (2016)
  • Author(s): Iwasaki T, Matsushita M, Nonaka D, Murakami I, Hayashi K.
  • Journal Title: Mod Pathol. Volume: 29 Issue: 1 Pages: 89-90
  • DOI: 10.1038/modpathol.2015.69
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Lower expression of CADM1 and higher expression of MAL in Merkel cell carcinomas are associated with Merkel cell polyomavirus infection and better prognosis. (2016)
  • Author(s): Takeshi Iwasaki, Michiko Matsushita, Daisuke Nonaka, Keiko Nagata, Masako Kato, Satoshi Kuwamoto, Ichiro Murakami, Kazuhiko Hayashi
  • Journal Title: Hum Pathol Volume: 48 Pages: 1-8
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Thyrotropin receptor antibody (TRAb)-IgM levels are markedly higher than TRAb-IgG levels in Graves’ disease patients and controls, and TRAb-IgM production is related to EBV reactivation. (2016)
  • Author(s): K Kumata, K Nagata, M Matsushita, S Kuwamoto, M Kato, I Murakami, S Fukata, K Hayashi
  • Journal Title: Viral Immunol. Volume: 29 Issue: 8 Pages: 459-463
  • DOI: 10.1089/vim.2016.0043
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Lower expression of CADM1 and higher expression of MAL in Merkel cell carcinomas are associated with Merkel cell polyomavirus infection and better prognosis. (2016)
  • Author(s): Iwasaki T, Matsushita M, Nonaka D, Nagata K, Kato M, Kuwamoto S, Murakami I, Hayashi K
  • Journal Title: Hum Pathol. Volume: 48 Pages: 1-8
  • DOI: 10.1016/j.humpath.2015.09.030
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Low prevalence of Merkel cell polyomavirus with low viral loads in oral and maxillofacial tumours or tumour-like lesions from immunocompetent patients: Absence of Merkel cell polyomavirus-associated neoplasms. (2015)
  • Author(s): Tanio S, Matsushita M, Kuwamoto S, Horie Y, Kodani I, Murakami I, Ryoke K, Hayashi K.
  • Journal Title: Mol Clin Oncol. Volume: 3 Pages: 1301-1306
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Phosphohistone-H3 (PHH3) is prognostic relevant in Merkel cell carcinomas but Merkel cell polyomavirus is a more powerful prognostic factor than AJCC clinical stage, PHH3, Ki-67 or mitotic indices. (2015)
  • Author(s): Iwasaki T, Matsushita M, Nonaka D, Kato M, Nagata K, Murakami I, Hayashi K.
  • Journal Title: Pathol Int. 2015 Aug;65(8):404-9. doi: 10.1111/pin.12305. Volume: 65 Issue: 8 Pages: 404-409
  • DOI: 10.1111/pin.12305
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Multiple Skin Cancers in a Renal Transplant Recipient: A Patient Report with Analyses of Human Papillomavirus and Human Polyomavirus Infection. (2015)
  • Author(s): Kaneda T, Matsushita M, Iwasaki T, Ishiguro N, Koide T, Hayashi K, Kitamura Y.
  • Journal Title: Yonago Acta Med. Volume: 58 Pages: 145-150
  • NAID: 120005663723
  • Peer Reviewed / Open Access
• [Journal Article] Acute-phase ITIH4 levels distinguish multi-system from single-system Langerhans cell histiocytosis via plasma peptidomics (2015)
  • Author(s): Murakami I, Oh Y, Morimoto A, Sano H, Kanzaki S, Matsushita M, Iwasaki T, Kuwamoto S, Kato M, Nagata K, Hayashi K, Imashuku S, Gogusev J, Jaubert F, Oka T, Yoshino T.
  • Journal Title: Clin Proteomics. Volume: 12 Issue: 1 Pages: 16-16
  • DOI: 10.1186/s12014-015-9089-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Interleukin-1 loop model for pathogenesis of Langerhans cell histiocytosis (2015)
  • Author(s): Murakami I, Matsushita M, Iwasaki T, Kuwamoto S, Kato M, Nagata K, Horie Y, Hayashi K, Imamura T, Morimoto A, Imashuku S, Gogusev J, Jaubert F, Takata K, Oka T, Yoshino T.
  • Journal Title: Cell Commun Signal Volume: 13 Issue: 1 Pages: 13-13
  • DOI: 10.1186/s12964-015-0092-z
  • Peer Reviewed / Open Access
• [Journal Article] Establishment of a Langerhans cell histiocytosis lesion cell line with dermal dendritic cell characteristics. (2015)
  • Author(s): Murakami I, Gogusev J, Jaubert F, Matsushita M, Hayashi K, Miura I, Tanaka T, Oka T, Yoshino T.
  • Journal Title: Oncol Rep. Volume: 33 Issue: 1 Pages: 171-8
  • DOI: 10.3892/or.2014.3567
  • Peer Reviewed
• [Journal Article] Comparison of Akt/mTOR/4E-BP1 pathway signal activation and mutations of PIK3CA in Merkel cell polyomavirus-positive and Merkel cell polyomavirus-negative carcinomas. (2015)
  • Author(s): Iwasaki T, Matsushita M, Nonaka D, Kuwamoto S, Kato M, Murakami I, Nagata K, Nakajima H, Sano S, Hayashi K.
  • Journal Title: Hum Pathol. Volume: 46 Issue: 2 Pages: 210-6
  • DOI: 10.1016/j.humpath.2014.07.025
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Immunoglobulin expressions are only associated with MCPyV-positive Merkel cell carcinomas but not with MCPyV-negative ones: comparison of prognosis. (2014)
  • Author(s): Murakami I, Takata K, Matsushita M, Nonaka D, Iwasaki T, Kuwamoto S, Kato M, Mohri T, Nagata K, Kitamura Y, Yoshino T, Hayashi K.
  • Journal Title: Am J Surg Pathol. Volume: 38 Issue: 12 Pages: 1627-1635
  • DOI: 10.1097/pas.0000000000000279
  • Peer Reviewed
• [Journal Article] A new in situ hybridization and immunohistochemistry with a novel antibody to detect small T-antigen expressions of Merkel cell polyomavirus (MCPyV). (2014)
  • Author(s): Matsushita M, Nonaka D, Iwasaki T, Kuwamoto S, Murakami I, Kato M, Nagata K, Kitamura Y, Hayashi K.
  • Journal Title: Diagn Pathol Volume: 9 Issue: 1 Pages: 65-65
  • DOI: 10.1186/1746-1596-9-65
  • Peer Reviewed / Open Access
• [Journal Article] High viral load of Merkel cell polyomavirus DNA sequences in Langerhans cell sarcoma tissues. (2014)
  • Author(s): Murakami I, Matsushita M, Iwasaki T, Kuwamoto S, Kato M, Horie Y, Hayashi K, Gogusev J, Jaubert F, Nakamoto S, Yamakawa M, Nakamine H, Takata K, Oka T, Yoshino T.
  • Journal Title: Infect Agent Cancer Volume: 9 Issue: 1 Pages: 15-15
  • DOI: 10.1186/1750-9378-9-15
  • Peer Reviewed / Open Access
• [Journal Article] Merkel cell polyomavirus (MCPyV) strains in Japanese merkel cell carcinomas (MCC) are distinct from Caaucasian type MCPyVs: genetic variability and phyllogeeny of MCPyV genomes oobtained from Japanese MCPyV-infected MCCs (2014)
  • Author(s): Matsushita M,Iwasaki T, Kuwamoto S, Kato M, Nagata K, Murakami I, Kitamura Y, Hayashi K
  • Journal Title: Virus Genes Volume: 48 Issue: 2 Pages: 233-242
  • DOI: 10.1007/s11262-013-1023-y
  • Peer Reviewed
• [Journal Article] Merkel cell polyomavirus DNA sequences in peripheral blood and tissues from patients with Langerhans cell histiocytosis. (2014)
  • Author(s): Murakami I, Matsushita M, Iwasaki T, Kuwamoto S, Kato M, Horie Y, Hayashi K, Imamura T, Morimoto A, Imashuku S, Gogusev J, Jaubert F, Takata K, Oka T, Yoshino T.
  • Journal Title: Hum Pathol. Volume: 45 Issue: 1 Pages: 119-126
  • DOI: 10.1016/j.humpath.2013.05.028
  • Peer Reviewed
• [Presentation] Expression of a long non-coding RNA NEAT1 is significantly higher in MCPyV-positive Merkel cell carcinomas than MCPyV-negative ones. (2016)
  • Author(s): Gen Akizuki, Katsutoshi Imamura, Toshimichi Yamada, Aiko Sato, Rena Mizutani, Michiko Matsushita, Takeshi Iwasaki, Daisuke Nonaka, Satoshi Kuwamoto, Keiko Nagata, Masako Kato, Nobuyoshi Akimitsu, Kazuhiko Hayashi
  • Organizer: European Congress of Patholgy
  • Place of Presentation: Cologne, Germany
  • Year and Date: 2016-09-25
  • Int'l Joint Research
• [Presentation] The relations of JAK-STAT signaling expressions to MCPyV-infection and outcome in Merkel cell carcinoma. (2016)
  • Author(s): Michiko Matsushita, Takeshi Iwasaki, Daisuke Nonaka, Satoshi Kuwamoto, Keiko Nagata, Masako Kato, Yukisato Kitamura, Kazuhiko Hayashi
  • Organizer: 28th European Congress of Patholgy
  • Place of Presentation: Cologne, Germany
  • Year and Date: 2016-09-25
  • Int'l Joint Research
• [Presentation] Biphasic production of immunoglobulin from EBV reactivated PBMCs in Graves’ disease patients and controls (2016)
  • Author(s): Keiko Nagata, Keisuke Kumata, Yuji Nakayama, Yukio Satoh, Michiko Matsushita, Ichiro Murakami, Satoshi Kuwamoto, Masako Kato, Hirotsugu Sugihara, Kazuhiko Hayashi
  • Organizer: 28th European Congress of Patholgy
  • Place of Presentation: Cologne, Germany
  • Year and Date: 2016-09-25
  • Int'l Joint Research
• [Presentation] メルケル細胞癌におけるJAK-STAT経路活性化とMCPyVおよび予後との関 係 (2016)
  • Author(s): 松下倫子、岩崎健、野中大輔、桑本聡史、長田佳子、加藤雅子、北村幸郷、林 一彦
  • Organizer: 第105回病理学会総会
  • Place of Presentation: 仙台国際センター、（宮城県仙台市）
  • Year and Date: 2016-05-12
• [Presentation] メルケル細胞癌におけるHedgehog signal発現とMCPyV感染および予後 との関連 (2016)
  • Author(s): 黒見晃行、松下倫子, 岩崎健、野中大輔、桑本聡史、長田佳子、加藤雅子、北村幸郷、林 一彦
  • Organizer: 第105回病理学会総会
  • Place of Presentation: 仙台国際センター、（宮城県仙台市）
  • Year and Date: 2016-05-12
• [Presentation] Higher CADM1 expression and lower MAL expression in Merkel cell carcinomas (MCCs) are associated with MCPyV-negative MCCs and unfavorable outcome (2015)
  • Author(s): Takeshi Iwasaki, Michiko Matsushita, Daisuke Nonaka, Ichiro Murakami, Masako Kato, Satoshi Kuwamoto, Keiko Nagata, Kazuhiko Hayashi
  • Organizer: 27th European Congress of Pathology
  • Place of Presentation: Belgrade, Serbia,
  • Year and Date: 2015-09-09
  • Int'l Joint Research
• [Presentation] Activation-induced deaminase (AID) gene expressions in Merkel cell carcinomas.by immunohistochemical and molecular analysis (2015)
  • Author(s): Michiko Matsushita, Takeshi Iwasaki, Satoshi Kuwamoto, Daisuke Nonaka, Keiko Nagata, Ichiro Murakami, Masako Kato, Yukisato Kitamura, Kazuhiko Hayashi
  • Organizer: 27th European Congress of Pathology
  • Place of Presentation: Belgrade, Serbia,
  • Year and Date: 2015-09-05
  • Int'l Joint Research
• [Presentation] Epstein-Barr virus reactivation stimulates the expression of activation-induced cytidine deaminase in PBMCs from Graves’ disease patients and healthy controls (2015)
  • Author(s): Keiko Nagata, Yuji Nakayama, Yukio Satoh, Keisuke Kumata, Michiko Matsushita, Shunsuke Tanio, Ichiro Murakami, Satoshi Kuwamoto, Masako Kato, Hirotsugu Sugihara, Kazuhiko Hayashi
  • Organizer: 27th European Congress of Pathology
  • Place of Presentation: Belgrade, Serbia
  • Year and Date: 2015-09-05
  • Int'l Joint Research
• [Presentation] 多変量解析によるメルケル細胞癌の予後予測因子の検討 (2015)
  • Author(s): 桑本聡史、松下倫子、野中大輔、岩崎健、村上一郎、加藤雅子、林一彦
  • Organizer: 第１０4回日本病理学会総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-04-30
• [Presentation] メルケル細胞癌のポリオーマウイルス(MCPyV)陽性群と陰性群におけるB細胞関連因子と免疫グロブリン発現の比較検討 (2014)
  • Author(s): Kazuhiko Hayashi, Daisuke Nonaka, Michiko Matsushita, Katsuyoshi Takata, Takeshi Iwasaki, Satoshi Kuwamoto, Masako Kato, Keiko Nagata, Yukisato Kitamura, Tadashi Yoshino, Ichiro Murakami
  • Organizer: 日本ウイルス学会
  • Place of Presentation: 横浜市、パシフィコ横浜
  • Year and Date: 2014-11-10 – 2014-11-12
• [Presentation] Comparative analysis of B cell-related marker and immunoglobulin expressions between MCPyV-positive and MCPyV-negative Merkel cell carcinomas (2014)
  • Author(s): Kazuhiko Hayashi, Daisuke Nonaka, Michiko Matsushita, Katsuyoshi Takata, Takeshi Iwasaki, Satoshi Kuwamoto, Masako Kato, Keiko Nagata, Yukisato Kitamura, Tadashi Yoshino, Ichiro Murakami
  • Organizer: 26th European Congress of Pathology
  • Place of Presentation: ExCel, London, UK
  • Year and Date: 2014-08-30 – 2014-09-03
• [Presentation] Expressions of p63 or/and its isoform, p40, are not correlated with the prognosis of Japanese and British patients with Merkel cell carcinoma (2014)
  • Author(s): Michiko Matsushita, Satoshi Kuwamoto, Daisuke Nonaka, Takeshi Iwasaki, Keiko Nagata, Ichiro Murakami, Masako Kato, Yukisato Kitamura, Kazuhiko Hayashi
  • Organizer: 26th European Congress of Pathology
  • Place of Presentation: ExCel, London, UK
  • Year and Date: 2014-08-30 – 2014-09-03
• [Presentation] TRAbs production induced by Epstein-Barr virus reactivation in cultured-PBMCs from Graves’ disease patients and healthy controls (2014)
  • Author(s): Keiko Nagata, Yuji Nakayama, Katsumi Higaki, Hiromi Miyauchi, Michiko Matsushita, Satoshi Kuwamoto, Masako Kato, Ichiro Murakami, Takeshi Iwasaki, Hiroshi Kimura, Kazuhiko Hayashi
  • Organizer: 26th European Congress of Pathology
  • Place of Presentation: ExCel, London, UK
  • Year and Date: 2014-08-30 – 2014-09-03
• [Presentation] メルケル細胞癌におけるp63及びp40の発現と生物学的悪性度との相関に関する検討 (2014)
  • Author(s): 松下倫子、桑本聡史、野中大輔、岩崎健、村上一郎、加藤雅子、北村幸郷、林一彦
  • Organizer: 日本病理学会
  • Place of Presentation: 広島市、広島国際会議場
  • Year and Date: 2014-04-24 – 2014-04-26