Anticancer effects based on core fucose

• Project/Area Number: 15K14408
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Tumor therapeutics
• Research Institution: Tohoku Medical and Pharmaceutical University
• Principal Investigator: GU Jianguo 東北医科薬科大学, 薬学部, 教授 (40260369)
• Co-Investigator(Renkei-kenkyūsha): FUKUDA Tomohiko 東北医科薬科大学, 薬学部, 准教授 (40433510)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: コアフコース / N型糖鎖 / がん / 細胞膜受容体 / 細胞内シグナル / 細胞増殖 / N-型糖鎖 / 受容体 / シグナル伝達 / 細胞移動

Outline of Final Research Achievements

The expression of core fucose catalyzed α1,6-fucosyltransferase (Fut8) has been known to be elevated in both liver and serum during the process of hepatocarcinogenesis (HCC) or in other cancers. However, functions of the increased core fucose in cancers remain poorly understood. In the present study, we used a well-established HCC model to investigate the functions of Fut8 in HCC, found that tumor incidence was greatly inhibited in Fut8-KO mice compared to wild-type mice, and the responses to growth factors such as EGF and HGF were decreased in Fut8 deficient cells compared to wild-type cells. Furthermore, Inhibition of core fucose by a small compound suppressed cancer cell proliferation and integrin-mediated cell migration, as well as colony formation and tumor xenograft efficacy. These results clearly described the importance of core fucose in cancer progression, suggesting the small compound might be a novel candidate for cancer therapy.

Research Products

• [Int'l Joint Research] 大連医科大学/武漢大学/南通大学(中国)
• [Journal Article] Alteration of N-glycan expression profile and glycan pattern of glycoproteins in human hepatoma cells after HCV infection. (2017)
  • Author(s): Xiang T, Yang G, Liu X, Zhou Y, Fu Z, Lu F, Gu J, Taniguchi N, Tan Z, Chen X, Xie Y, Guan F, Zhang XL
  • Journal Title: Biochim Biophys Acta Volume: 1861 Issue: 5 Pages: 1036-1045
  • DOI: 10.1016/j.bbagen.2017.02.014
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] N-Glycoform-dependent interactions of megalin with its ligands. (2017)
  • Author(s): Hirano M, Totani K, Fukuda T, Gu J, Suzuki A
  • Journal Title: Biochim Biophys Acta Volume: 1861 Issue: 1 Pages: 3106-3118
  • DOI: 10.1016/j.bbagen.2016.10.015
  • Peer Reviewed
• [Journal Article] A key regulator of cell adhesion: Identification and characterization of important N-glycosylation sites on integrin α5 for cell migration. (2017)
  • Author(s): Hang, Q., Isaji, T., Hou, S., Wang, Y., Fukuda, T. and Gu, J.
  • Journal Title: Mol. Cell. Biol. Volume: 37 Issue: 9
  • DOI: 10.1128/mcb.00558-16
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Transforming growth factor (TGF) β1 acted through miR-130b to increase integrin α5 to promote migration of colorectal cancer cells. (2016)
  • Author(s): Yi R., Li Y., Wang F., Gu J., Isaji T., Li J., Qi R., Zhu X. and Zhao Y.
  • Journal Title: Tumour Biol. Volume: 37 Issue: 8 Pages: 10763-73
  • DOI: 10.1007/s13277-016-4965-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] N-Glycosylation of integrin α5 acts as a switch for EGFR-mediated complex formation of integrin α5β1 to α6β4. (2016)
  • Author(s): Hang, Q., Isaji, T., Hou, S., Zhou, Y., Fukuda, T. and Gu, J.
  • Journal Title: Sci. Rep. Volume: 10 Issue: 1 Pages: 1-15
  • DOI: 10.1038/srep33507
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Disease-associated glycans on cell surface proteins. (2016)
  • Author(s): Takahashi M, Kizuka Y, Ohtsubo K, Gu J, Taniguchi N.
  • Journal Title: Molecular Aspects of Medicine Volume: 51 Pages: 56-70
  • DOI: 10.1016/j.mam.2016.04.008
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Importance of membrane-proximal N-glycosylation on integrin β1 in its activation and complex formation. (2016)
  • Author(s): Hou S, Hang Q, Isaji T, Lu J, Fukuda T, Gu J.
  • Journal Title: FASEB J. Volume: 30 Pages: 4120-4131
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Expression of N-acetylglucosaminyltransferase III suppresses α2,3 sialylation and its distinctive functions in cell migration are attributed to α2,6 sialylation levels. (2016)
  • Author(s): Lu, J., Isaji, T., Im, S., Fukuda, T., Kameyama, A. and Gu, J.
  • Journal Title: J. Biol. Chem. Volume: 291 Issue: 11 Pages: 5708-20
  • DOI: 10.1074/jbc.m115.712836
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Significance of β-Galactoside α2,6 Sialyltranferase 1 in Cancers (2015)
  • Author(s): Lu, J. and Gu, J.
  • Journal Title: Molecules Volume: 20 Issue: 5 Pages: 7509-27
  • DOI: 10.3390/molecules20057509
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Loss of α1,6-fucosyltransferase decreased hippocampal long-term potentiation: implications for core fucosylation in the regulation of AMPA receptor heteromerization and cellular signaling. (2015)
  • Author(s): Gu, W., Fukuda, T., Isaji, T., Hang, Q., Lee, H., Sakai, S., Morise, J., Mitoma, J., Higashi, H., Taniguchi, N., Yawo, H., Oka, S. and Gu, J.
  • Journal Title: J. Biol. Chem. Volume: 290 Issue: 28 Pages: 17566-75
  • DOI: 10.1074/jbc.m114.579938
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Integrin α5 Suppresses the Phosphorylation of Epidermal Growth Factor Receptor and Its Cellular Signaling of Cell Proliferation via N-Glycosylation (2015)
  • Author(s): Hang Q, Isaji T, Hou S, Im S, Fukuda T, Gu J.
  • Journal Title: J Biol Chem Volume: 290 Issue: 49 Pages: 29345-60
  • DOI: 10.1074/jbc.m115.682229
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Loss of α1,6-fucosyltransferase inhibits chemical-induced hepatocellular carcinoma and tumorigenesis by down-regulating several cell signaling pathways
  • Author(s): Yuqin Wang, Tomohiko Fukuda, Tomoya Isaji, Jishun Lu, Sanghun Im, Qinglei Hang, Wei Gu, Sicong Hou, Kazuaki Ohtsubo, Jianguo Gu
  • Journal Title: The FASEB Journal Volume: 29 Issue: 8 Pages: 3217-3227
  • DOI: 10.1096/fj.15-270710
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Functional analysis of N-glycosylation in neuroninflammation (2017)
  • Author(s): 張冬梅、福田友彦、顧建国
  • Organizer: 第２１回アジア地域招聘研究者研究発表会
  • Place of Presentation: 野村コンファレンスプラザ日本橋YUITO(東京都中央区）
• [Presentation] β4インテグリンはガレクチン３/N型糖鎖複合体を介して腫瘍悪性化のシグナルを促進する (2016)
  • Author(s): 苅谷慶喜、今野翠、顧建国
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜パシフィコ（神奈川県横浜市）
  • Year and Date: 2016-10-06
• [Presentation] The importance of N-glycosylation on integrin β1 in its activation and complex formation (2016)
  • Author(s): 侯 思聡、伊左治 知弥、杭 慶雷、福田 友彦、顧 建国
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-09-25
• [Presentation] N-glycosylation on Integrin α5 define active integrin α5β1 internalization to regulate cell migration (2016)
  • Author(s): 杭 慶雷、伊左治 知弥、侯 思聡、福田 友彦、顧 建国
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-09-25
• [Presentation] 細胞接着におけるN型糖鎖の機能発現と細胞内シグナル伝達 (2016)
  • Author(s): 顧 建国
  • Organizer: 第３５回日本糖質学会年会
  • Place of Presentation: 高知文化プラザかるぽーと（高知県高知市）
  • Year and Date: 2016-09-01
• [Presentation] PIKIIαによるインテグリンα3β1の制御とンN-型糖鎖調節 (2016)
  • Author(s): 伊左治 知弥、任 翔フン、福田 友彦、顧 建国
  • Organizer: 第３５回日本糖質学会年会
  • Place of Presentation: 高知文化プラザかるぽーと（高知県高知市）
  • Year and Date: 2016-09-01
• [Presentation] N-glycans in cell adhesion and EMT (2016)
  • Author(s): 顧建国
  • Organizer: 6th Charles Warren Workshop
  • Place of Presentation: 北海道大学（北海道札幌市）
  • Year and Date: 2016-08-23
  • Int'l Joint Research / Invited
• [Presentation] Roles of N-glycan in EMT and cellular signaling (2016)
  • Author(s): 顧 建国
  • Organizer: 2016年中国糖生物学学術会議
  • Place of Presentation: 中国南通市
  • Year and Date: 2016-08-05
  • Invited
• [Presentation] N-glycosylation on Integrin α5 serve as an on/off switch to regulate EGFR signaling (2016)
  • Author(s): 杭 慶雷、伊左治 知弥、侯 思聡、福田 友彦、顧 建国
  • Organizer: 日本生化学会東北支部
  • Place of Presentation: 弘前大学（青森県弘前市）
  • Year and Date: 2016-05-21
• [Presentation] N-glycosylation in cancer cells (2016)
  • Author(s): Jianguo Gu
  • Organizer: 南通大学薬理学国際人材研討会
  • Place of Presentation: 南通市（中国）
  • Year and Date: 2016-03-17
  • Invited
• [Presentation] Core fucose in liver and HCC (2016)
  • Author(s): 顧 建国
  • Organizer: 2016 Annual Symposium of Hubei Province Key Laboratory of Allergy and Immunology
  • Place of Presentation: 中国武漢市
  • Invited
• [Presentation] がん細胞接着とEMTにおける糖鎖の機能発現とその制御 (2016)
  • Author(s): 顧 建国
  • Organizer: 東北薬学支部会総会学術講演会
  • Place of Presentation: 東北大学（宮城県仙台市）
  • Invited
• [Presentation] 肝がんおよび肝再生におけるコアフコースの機能 (2015)
  • Author(s): 福田 友彦、顧 建国
  • 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 合同大会
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-12-01
• [Presentation] Roles for glycans in cell adhesion and migration (2015)
  • Author(s): Jianguo Gu
  • Organizer: 7th Asian Community of Glycoscience and Glycotechnology (ACGG)
  • Place of Presentation: ホテル松島大観荘（宮城県宮城郡）
  • Year and Date: 2015-11-12
  • Int'l Joint Research / Invited
• [Presentation] Loss of FUT8 inhibits chemical-induced hepatocellular carcinoma and tumorigenesis by down-regulating multiple cellular signaling (2015)
  • Author(s): Jianguo Gu
  • Organizer: 23rd International Symposium on Glycoconjugates
  • Place of Presentation: スプリット（クロアチア）
  • Year and Date: 2015-09-15
  • Int'l Joint Research
• [Presentation] 肝がん形成におけるコアフコースの機能 (2015)
  • Author(s): 顧建国
  • Organizer: 第９回東北糖鎖研究会•東北薬科大学分子生体膜研究所シンポジウム
  • Place of Presentation: 東北医科薬科大学（宮城県仙台市）
  • Year and Date: 2015-09-04
  • Invited
• [Presentation] Fut8の機能解析：肝臓および脳神経組織におけるコアフコースの重要性 (2015)
  • Author(s): 福田 友彦、王 玉琴、伊左治 知弥、顧 建国
  • Organizer: 第９回東北糖鎖研究会•東北薬科大学分子生体膜研究所シンポジウム
  • Place of Presentation: 東北医科薬科大学（宮城県仙台市）
  • Year and Date: 2015-09-04
• [Presentation] Hepatocellular carcinoma and core fucose (2015)
  • Author(s): Jianguo Gu
  • Organizer: Institute of Biomedical Sciences of Fudan University Seminar
  • Place of Presentation: 中国上海
  • Year and Date: 2015-08-12
  • Invited
• [Remarks] 東北医科薬科大学 分子生体膜研究所 細胞制御学
  • URL: http://www.tohoku-mpu.ac.jp/laboratory/drg/index.html
• [Remarks] 東北医科薬科 分子生体膜研究所 細胞制御学
  • URL: http://www.tohoku-mpu.ac.jp/laboratory/drg/index.html
• [Patent(Industrial Property Rights)] 抗コアフコシル化ヒト免疫グロブリンＧ抗体 (2016)
  • Inventor(s): 谷口 直之、顧建国、小野 達也、 椎田 真史、真木 賢太
  • Industrial Property Rights Holder: 谷口 直之、顧建国、小野 達也、 椎田 真史、真木 賢太
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-179944
  • Filing Date: 2016-09-14