Mechanisms for innate immune check-point generated by siglecs and sialic acid-containing carbohydrates

• Project/Area Number: 15K15080
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Chubu University
• Principal Investigator: FURUKAWA Koichi 中部大学, 生命健康科学部, 教授 (80211530)
• Co-Investigator(Kenkyū-buntansha): 山内 祥生 東京大学, 大学院農学生命科学研究科(農学部), 特任准教授 (00444878) ; 橋本 登 徳島大学, 大学院医歯薬学研究部(歯学系), 助教 (90712365)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: シグレック / 自然免疫 / シアル酸 / チェックポイント / 癌免疫 / 糖鎖 / 細胞傷害 / 糖脂質 / シグナル / 単球 / マクロファージ / アストロサイトーマ

Outline of Final Research Achievements

Sialic acid-containing cancer-associated carbohydrates are involved in the malignant properties of tumor cells, while innate immune cells such as NK and monocyte-macrophages express sialic-acid-recognizing lectins such as siglec-7 and 9. Then, significance and application for therapeutics of their interaction have been analyzed.
Analyses of carbohydrate structures recognized by siglecs and of their carrier molecules were performed, showing that siglec-7 recognized disialyl glycolipids such as GD3, and tri-sialylated carbohydrate-conjugated proteins. It was also shown that signals mediated by siglec-7 suppressed NK activity. Furthermore, it was demonstrated that GD3 with hydroxylated long chain base at C4 was not recognized by siglec-7, and also glycolipids containing hydroxylated ceramides scarcely localized in lipid rafts.

Research Products

• [Int'l Joint Research] Dundee University(英国)
• [Journal Article] ASC amino acid transporter 2, defined by enzyme-mediated activation of radical sources, enhances malignancy of GD2-positive small-cell lung cancer. (2018)
  • Author(s): Nobutoshi Esaki, Yuki Ohkawa, Noboru Hashimoto, Yuhsuke Tsuda, Yuhsuke Ohmi, Robiul H. Bhuiyan, Norihiro Kotani, Koichi Honke, Atsushi Enomoto, Masahide Takahashi, Keiko Furukawa, Koichi Furukawa.
  • Journal Title: Cancer sci. Volume: 109 Issue: 1 Pages: 141-153
  • DOI: 10.1111/cas.13448
  • Peer Reviewed / Open Access
• [Journal Article] Glycolipids: Essential regulator of neuro-inflammation, metabolism and gliomagenesis. (2017)
  • Author(s): Koichi Furukawa, Yuhsuke Ohmi, Shuting Ji, Pu Zhang, Robiul H. Bhuiyan, Yuki Ohkawa, Orie Tajima, Noboru Hashimoto, Keiko Furukawa
  • Journal Title: Biochim. Biophys. Acta Volume: 1861 Issue: 10 Pages: 2479-2484
  • DOI: 10.1016/j.bbagen.2017.06.007
  • Peer Reviewed
• [Journal Article] Functional characterization of a novel GFI1B mutation causing congenital macrothrombocytopenia (2016)
  • Author(s): Bhuiyan RH, Yuji Kondo, Noriyo Tokuda, Ryota Mori, Keiko Furukawa, Koichi Furukawa
  • Journal Title: Glycobiology Volume: 26 Pages: 984-998
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Factors secreted from dental pulp stem cells show multifaceted benefits for treating experimental rheumatoid arthritis. (2016)
  • Author(s): Ishikawa J, Takahashi N, Matsumoto T, Yoshioka Y, Yamamoto N, Nishikawa M, Hibi H, Ishigro N, Ueda M, Furukawa K, Yamamoto A.
  • Journal Title: Bone. Volume: 83 Pages: 210-219
  • DOI: 10.1016/j.bone.2015.11.012
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Expression of B4GALNT1, an essential glycosyltransferase for the synthesis of complex gangliosides, suppresses BACE1 degradation and modulates APP processing (2016)
  • Author(s): Yamaguchi T, Yamauchi Y, Furukawa K, Ohmi Y, Ohkawa Y, Zhang Q, Okajima T, Furukawa K
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 34505-34505
  • DOI: 10.1038/srep34505
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Soluble Siglec-9 suppresses arthritis in a collagen-induced arthritis mouse model and inhibits M1 activation of RAW264.7 macrophages. (2016)
  • Author(s): Matsumoto T, Takahashi N, Kojima T, Yoshioka Y, Ishikawa J, Furukawa K, Ono K, Sawada M, Ishiguro N, Yamamoto A.
  • Journal Title: Arthritis Research & Therapy Volume: 18（１） Issue: 1 Pages: 133-133
  • DOI: 10.1186/s13075-016-1035-9
  • NAID: 120006937643
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Ganglioside GD3 enhances invasiveness via Yes activation by forming a complex of GD3/PDGFRα/Yes in gliomas (2015)
  • Author(s): Yuki Ohkawa, Hiroyuki Momota, Akira Kato, Noboru Hashimoto, Yuhsuke Tsuda, Norihiro Kotani, Koichi Honke, Akio Suzumura, Keiko Furukawa, Yuhsuke Ohmi, Atsushi Natsume, Toshihiko Wakabayashi and *Furukawa K
  • Journal Title: J. Biol. Chem. Volume: 290 Issue: 32 Pages: 16043-16058
  • DOI: 10.1074/jbc.m115.708834
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Regulatory function of glycosphingolipids in the inflammation and degeneration. (2015)
  • Author(s): Furukawa K., Ohmi Y., Kondo Y., Ohkawa Y., Tajima O. and Furukawa K
  • Journal Title: Arch Biochem Biophys Volume: 571 Pages: 58-65
  • DOI: 10.1016/j.abb.2015.02.007
  • Peer Reviewed / Open Access
• [Journal Article] Akt-girdin signaling in cancer-associated fibroblasts contributes to tumor progression (2015)
  • Author(s): Yumiko Yamamura, Naoya Asai, Atsushi Enomoto, Takuya Kato, Shinji Mii, Yuji Kondo, Kaori Ushida, Kaoru Niimi, Nobuyuki Tsunoda, Masato Nagino, Shu Ichihara, Koichi Furukawa, Kengo Maeda, Toyoaki Murohara, Masahide Takahashi
  • Journal Title: Cancer Research Volume: 75 Issue: 5 Pages: 813-823
  • DOI: 10.1158/0008-5472.can-14-1317
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Regulation of cell signaling by ganglioside GD3/GD2 in gliomas (2017)
  • Author(s): Koichi Furukawa, Yuki Ohkawa, Kei Kaneko, Noboru Hashimoto, Zhang Pu, Robiul H. Bhuiyan, Yuhsuke Ohmi, Keiko Furukawa
  • Organizer: GLYCO XXIV
  • Int'l Joint Research / Invited
• [Presentation] 癌関連糖脂質GD3とSiglec-7による腫瘍免疫監視逃避機構の解明 (2016)
  • Author(s): 橋本 登, 伊藤静香, 池田和貴, 土田明子, Paul R. Crocker, 古川圭子, 田口 良, 古川鋼一
  • Organizer: 第39回 日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-12-01
• [Presentation] グリオーマにおいてGD3発現に伴って発現する遺伝子群の同定 (2016)
  • Author(s): 大川祐樹, 野田誠也, 百田洋之, 加藤 彰, 張 璞, 古川圭子, 大海雄介, 夏目敦至, 若林俊彦, 古川鋼一
  • Organizer: 第75回 日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-06
• [Presentation] GD3-expressing glioma reduce M1-like phenotypes of glioma-associated microglia/macrophages via inflammatory cytokines (2016)
  • Author(s): 張 璞, 大川祐樹, RH. Bhuiyan, 大海雄介, 高野舞子, 古川圭子, 古川鋼一
  • Organizer: 第75回 日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-06
• [Presentation] TNFαとcAMPはメラノサイトにおいてメラノーマ関連糖鎖合成酵素遺伝子の発現を分別的に制御する (2016)
  • Author(s): 竹内理香, 宮田麻衣子, ウプル ジャヤデワン, 田島織絵, 神戸真理子, 古川 鋼一, 古川圭子
  • Organizer: 第75回 日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-06
• [Presentation] 癌関連スフィンゴ糖脂質糖鎖による細胞形質の制御 (2016)
  • Author(s): 古川圭子, 神戸真理子, 大川祐樹, 大海雄介, 竹内理香, 田島織絵, 古川鋼一
  • Organizer: 第89回 日本生化学会大会
  • Place of Presentation: 仙台国際センター・東北大川内北キャンパス（宮城県仙台市）
  • Year and Date: 2016-09-25
• [Presentation] グリオーマにおいてガングリオシドGD3はPDGFRαの発現を誘導する (2016)
  • Author(s): 大川祐樹, 百田洋之, 加藤 彰, 橋本 登, 古川圭子, 大海雄介, 夏目敦至, 若林 俊彦, 古川鋼一
  • Organizer: 第35回 日本糖質学会年会
  • Place of Presentation: 文化プラザかるぽーと（高知県高知市）
  • Year and Date: 2016-09-01
• [Presentation] GD3は炎症性サイトカインを介してグリオーマ関連ミクログリアのM1様表現型を抑制する (2016)
  • Author(s): 張 璞, 大川祐樹, Bhuiyan RH, 百田洋介, 若林俊彦, 大海雄介, 古川圭子, 岡島徹也. 古川鋼一
  • Organizer: 第35回 日本糖質学会年会
  • Place of Presentation: 文化プラザかるぽーと（高知県高知市）
  • Year and Date: 2016-09-01
• [Presentation] 糖脂質糖鎖によるシグナルの制御のメカニズム (2015)
  • Author(s): 古川鋼一、大川祐樹、大海雄介、橋本登、古川圭子
  • Organizer: 第38回 日本分子生物学会年会 第88回 日本生化学会大会
  • Place of Presentation: 神戸ポートアイランド（神戸市）
  • Year and Date: 2015-12-04
  • Invited
• [Presentation] Gene expression analysis in mouse RAW264-7cells treated with Siglec-9 and MCP-1 (2015)
  • Author(s): TAKANO Maiko,HASIMOTO Nboru,OHKAWA Yuki ,MATUBARA Kohki,YAMAMOTO Akiko,FURUKAWA Keiko,FURUKAWA Koichi
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター（札幌市）
  • Year and Date: 2015-11-18
• [Presentation] Novel functions and mechanisms of complex carbo-hydrates elucidated by glycosyltransferase gene knockout (2015)
  • Author(s): Koichi Furukawa
  • Organizer: GLYCO23(第23回 国際糖鎖学会
  • Place of Presentation: クロアチア、スプリット
  • Year and Date: 2015-09-17
  • Int'l Joint Research / Invited
• [Book] Glyco-signals in Cancer (2016)
  • Author(s): Koichi Furukawa, Yuki Ohkawa, Yasuyuki Matsumoto, Yuhsuke Ohmi, Noboru Hashimoto, Keiko Furukawa Regulatory Mechanisms for Malignant Properties of Cancer Cells with Disialyl and Monosialyl Gangliosides
  • Publisher: Springer
• [Book] Lipid/rafts (2016)
  • Author(s): Koichi Furukawa, Yuhsuke Ohmi, Yuki Ohkawa, Noboru Hashimoto, Yuji Kondo, Orie Tajima, Keiko Furukawa
  • Publisher: Nova Science Publishers
• [Book] Gangliosides Regulate Tumor Properties: With Focus on the Suppression of Metastasis-Associated ppGalNAc-T13 with GM1. In Sugar Chains (2015)
  • Author(s): Koichi Furukawa, Yasuyuki Matsumoto, Qing Zhang, and Keiko Furukawa
  • Total Pages: 288
  • Publisher: Springer