Establishment of novel therapeutic strategy against neuroendocrine lung cancer through regulation of malignant neural phenotype

• Project/Area Number: 15K08360
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Dokkyo Medical University (2016-2017); Chiba University (2015)
• Principal Investigator: YAZAWA TAKUYA 獨協医科大学, 医学部, 教授 (50251054)
• Co-Investigator(Kenkyū-buntansha): 原 由紀子 東京医科大学, 医学部, 准教授 (40313267) ; 矢澤 華子 (佐藤 / 佐藤 華子) 獨協医科大学, 医学部, 講師 (60438132) ; 三好 洋 聖マリアンナ医科大学, 医学部, 助手 (80322519)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 肺癌 / 神経内分泌肺癌 / 非神経内分泌肺癌 / 形質転換 / 遺伝子治療 / 神経内分泌形質 / 非神経内分泌癌 / 神経内分泌癌 / リプログラミング現象

Outline of Final Research Achievements

We had experienced that POU3F4 or POU4F2 transgene made non-neuroendocrine lung cancer (NNELC) cells cause transformation to neuroendocrine lung cancer (NELC). Carrying out this study, it was clarified that the transformation from NNELC to NELC is a direct reprogramming phenomenon and that breakdown of a neural cell-specific NOTCH-HES pathway, which is activated by POU3F4/4F2 transgene, diminish neuroendocrine phenotype.

Research Products

• [Journal Article] Enhancement of glycolysis by inhibition of oxygen-sensing prolyl hydroxylases protects alveolar epithelial cells from acute lung injury (2018)
  • Author(s): Tojo Kentaro、Tamada Nao、Nagamine Yusuke、Yazawa Takuya、Ota Shuhei、Goto Takahisa
  • Journal Title: The FASEB Journal Volume: 32 Issue: 4 Pages: 2258-2268
  • DOI: 10.1096/fj.201700888r
  • Peer Reviewed
• [Journal Article] Adenovirus vector expressing keratinocyte growth factor using CAG promoter impairs pulmonary function of mice with elastase-induced emphysema. (2017)
  • Author(s): Oki H, Yazawa T, Baba Y, Kanegae Y, Sato H, Sakamoto S, Goto T, Saito I, Kurahashi K.
  • Journal Title: Microbiol Immunol Volume: 61 Issue: 7 Pages: 264-271
  • DOI: 10.1111/1348-0421.12492
  • NAID: 40021258617
  • Peer Reviewed
• [Journal Article] Adrenaline aggravates lung injury caused by liver ischemia-reperfusion and high-tidal-volume ventilation in rats. (2016)
  • Author(s): Ota S, Yazawa T, Tojo K, Baba Y, Uchiyama M, Goto T, Kurahashi K.
  • Journal Title: J Intensive Care Volume: 4 Issue: 1 Pages: 8-8
  • DOI: 10.1186/s40560-016-0130-y
  • Peer Reviewed
• [Journal Article] Inhibition of prolyl hydroxylase attenuates fas ligand-induced apoptosis and lung injury in mice. (2016)
  • Author(s): Nagamine Y, Tojo K, Yazawa T, Takaki S, Baba Y, Goto T, Kurahashi K.
  • Journal Title: American Journal of Respiratory Cell and Molecular Biology Volume: 55 Pages: 878-888
  • Peer Reviewed
• [Journal Article] PROX1 promotes secretory granule formation in medullary thyroid cancer cells (2016)
  • Author(s): Ishii J, Yazawa T, Chiba T, Shishido-Hara Y, Arimasu Y, Sato H, Kamma H
  • Journal Title: Endocrinology Volume: 157 Pages: 1289-1298
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Edaravone prevents lung injury induced by hepatic ischemia-reperfusion (2015)
  • Author(s): Uchiyama M, Tojo K, Yazawa T, Ota S, Goto T, Kurahashi K
  • Journal Title: J Surg Res Volume: 194 Issue: 2 Pages: 551-557
  • DOI: 10.1016/j.jss.2014.11.011
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Recent advances in histogenesis research of lung neuroendocrine cancers: Evidence obtained from functional analyses of primitive neural/neuroendocrine cell-specific transcription factors (2015)
  • Author(s): Yazawa T
  • Journal Title: Pathol Int Volume: 65 Issue: 6 Pages: 277-285
  • DOI: 10.1111/pin.12267
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] High-grade fetal adenocarcinoma of the lung is a tumour with a fetal phenotype that shows diverse differentiation including high-grade neuroendocrine carcinoma: a clinicopathological, immunohistochemical and mutational study of 20 cases (2015)
  • Author(s): Suzuki M, Yazawa T, Ota S, Morimoto J, Yoshino I, Yamanaka S, Inayama Y, Kawabata Y, Shimizu Y, Komatsu M, Notohara K, Koda K, Nakatani Y
  • Journal Title: Histopathology Volume: 67 Issue: 6 Pages: 806-816
  • DOI: 10.1111/his.12711
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] CD8-positive T-cell lymphoproliferative disorder associated with Epstein-barr virus-infected B-cells in a rheumatoid arthritis patient under methotrexate treatment. (2014)
  • Author(s): Koji H, Yazawa T, Nakabayashi K, Fujioka Y, Kamma H, Yamada A.
  • Journal Title: Mod Rheumatol Volume: 24 Issue: 2 Pages: 1-5
  • DOI: 10.3109/14397595.2013.850613
  • Peer Reviewed
• [Presentation] POU3F4/4F2遺伝子導入により肺癌細胞に惹起されたダイレクトリプログラミング現象 (2017)
  • Author(s): 矢澤華子、石井順、宍戸-原由紀子、柏木維人、平松千恵、菅間博、矢澤卓也
  • Organizer: 第106回日本病理学会総会
• [Presentation] POU3F4/4F2遺伝子導入により肺癌細胞に惹起されたダイレクトリプログラミング現象 (2017)
  • Author(s): 矢澤華子、石井順、平松千恵、宍戸-原由紀子、菅間博、矢澤卓也
  • Organizer: 第21回日本臨床内分泌病理学会総会
• [Presentation] Inhibition of prolyl hydroxylase attenuates Fas ligand-induced apoptosis and lung injury in mice (2016)
  • Author(s): Nagamine Y, Tojo K, Yazawa T, Takaki S, Baba Y, Goto T, Kurahashi K
  • Organizer: ATS 2016
  • Place of Presentation: Moscone Center, San Francisco, California, USA
  • Year and Date: 2016-05-13
• [Presentation] Inhibition of prolyl hydroxylase attenuates Fas ligand-induced apoptosis and lung injury in mice (2016)
  • Author(s): Nagamine Y, Tojo K, Yazawa T, Takaki S, Baba Y, Goto T, Kurahashi K
  • Organizer: 日本呼吸器学会
  • Place of Presentation: 国立京都国際会館（京都市左京区）
  • Year and Date: 2016-04-08
• [Presentation] SLC26A7が甲状腺の新たなヨードトランスポーターである可能性について (2016)
  • Author(s): 石井順、山野環、千葉知宏、山本浩之、平野浩一、矢澤卓也、菅間博
  • Organizer: 日本臨床内分泌病理学会
  • Place of Presentation: 帝京大学板橋キャンパス大学棟（東京都板橋区）
• [Presentation] PROX1は甲状腺髄様癌の内分泌顆粒形成に関与する (2015)
  • Author(s): 石井 順、矢澤卓也、千葉知宏、有益 優、菅間 博
  • Organizer: 日本内分泌病理学会
  • Place of Presentation: アバンセ、佐賀県佐賀市
  • Year and Date: 2015-10-24
• [Presentation] 肺癌の分子病理学から見た組織病理学、細胞学 (2015)
  • Author(s): 矢澤卓也
  • Organizer: 平成27年度千葉県臨床細胞学会
  • Place of Presentation: 君津中央病院、千葉県君津市
  • Year and Date: 2015-07-11
  • Invited
• [Presentation] 甲状腺髄様癌の内分泌顆粒形成におけるPROX1の役割について (2015)
  • Author(s): 石井 順、小島薫子、千葉知宏、住石 歩、有益 優、宍戸-原由紀子、佐藤華子、矢澤卓也、菅間 博
  • Organizer: 第104回日本病理学会総会
  • Place of Presentation: 名古屋国際会議場、愛知県名古屋市
  • Year and Date: 2015-04-30
• [Presentation] Analysis of high-grade fetal adenocarcinoma of the lung (2015)
  • Author(s): 鈴木理樹、矢澤卓也、太田 聡、森本淳一、吉野一郎、中谷行雄
  • Organizer: 第104回日本病理学会総会
  • Place of Presentation: 名古屋国際会議場、愛知県名古屋市
  • Year and Date: 2015-04-30
• [Presentation] 肺内分泌腫瘍におけるBRN2, ASCL1, TTF1, P53の発現性の検討 (2015)
  • Author(s): 遠藤哲哉、石井順、榮田昌史、藤原正親、宍戸-原由紀子、下山田博明、平野和彦、寺戸雄一、菅間博、矢澤卓也、遠藤俊輔
  • Organizer: 第115回日本外科学会定期学術集会
  • Place of Presentation: 名古屋国際会議場、愛知県名古屋市
  • Year and Date: 2015-04-16
• [Remarks] 獨協医科大学病理学 研究内容
  • URL: http://www.dokkyomed.ac.jp/dep-m/pathology/index.html