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新規がん遺伝子THG-1の生体機能の解明と分子診断・治療法の開発

Research Project

Project/Area Number 22K06995
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 49030:Experimental pathology-related
Research InstitutionTohoku University

Principal Investigator

鈴木 裕之  東北大学, 医学系研究科, 准教授 (70375509)

Co-Investigator(Kenkyū-buntansha) 鄭 齢  筑波大学, 医学医療系, 助教 (70833565)
Project Period (FY) 2022-04-01 – 2025-03-31
Project Status Granted (Fiscal Year 2023)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2024: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2023: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
KeywordsTHG-1 / TSC22D4 / Interleukin-1 / TRAF6 / NRBP1 / Squamous cell carcinoma / 扁平上皮がん / 炎症 / タンパク質間相互作用 / がん治療薬
Outline of Research at the Start

扁平上皮がんは重層扁平上皮細胞を主な起源とし、食道、皮膚、肺などに発生する予後不良のがんである。正常扁平上皮の構成細胞は基底部に存在する幹細胞から供給され、それらが増殖、重層化、分化という複雑な過程を経て形成されるが、その詳しい形成機構、また発がん機構については不明である。本研究では扁平上皮の増殖、分化、及びがん化におけるTHG-1/TSC22D4の役割を明らかにし、そのリン酸化、変異、結合タンパクを標的にした分子腫瘍マーカーの開発、及びスクリーニングで新たに同定したタンパク質間相互作用阻害剤によるがん治療への応用を目指す。

Outline of Annual Research Achievements

The inflammatory microenvironment promotes tumor cell proliferation and immune cell infiltration. However, the mechanism of continuous activation of inflammatory response in tumor has not been fully elucidated. In this study, we found that THG-1/TSD22D4 activates the IL-1 signaling pathways in SCCs. The RNA sequencing analysis revealed that THG-1 overexpression en-hances the transcription of NF-κB targets including IL1A, IL1B, TNFA, and IL8. Furthermore, THG-1 knockdown reduced the responsiveness to IL-1 through suppression of NF-κB nuclear translocation. To elucidate the mechanism, we focused on a THG-1 interacting protein, NRBP1. We found that NRBP1 facilitates the degradation of TRAF6 through its E3 ubiquitin ligase activ-ity. THG-1 bound to NRBP1 and suppressed the degradation of TRAF6. Furthermore, THG-1 knockdown reduced TRAF6 abundance and NF-κB activity in SCC cells. Public database anal-yses of head and neck SCC revealed that high expression of THG-1 is associated with activation of the IL-1 and TNF pathways, which share TRAF6 in the signal transductions. Finally, THG-1 abundance in laryngeal SCC specimens is elevated in patients with recurrence. These results indicated that THG-1 drives the self-sufficiency of the IL-1-mediated inflammatory response through suppression of TRAF6 degradation.

Current Status of Research Progress
Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

THG-1による炎症反応の自己充足化の分子メカニズムを解明する論文の投稿、改訂に至ったため。

Strategy for Future Research Activity

投稿した論文の改訂を進め、論文受理を目指す。
またTHG-1によるストレス耐性の分子メカニズムの解明を、新規結合タンパク質を通じて明らかにする。

Report

(2 results)
  • 2023 Research-status Report
  • 2022 Research-status Report
  • Research Products

    (10 results)

All 2023 2022

All Journal Article (6 results) (of which Peer Reviewed: 6 results,  Open Access: 6 results) Presentation (4 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Promotion of squamous cell carcinoma tumorigenesis by oncogene‐mediated THG‐1/TSC22D4 phosphorylation2023

    • Author(s)
      Goto Nohara、Suzuki Hiroyuki、Zheng Ling、Okano Yasuhito、Okita Yukari、Watanabe Yukihide、Kato Yukinari、Kato Mitsuyasu
    • Journal Title

      Cancer Science

      Volume: 114 Issue: 10 Pages: 3972-3983

    • DOI

      10.1111/cas.15934

    • Related Report
      2023 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Development of a Novel Anti-CD44 Variant 5 Monoclonal Antibody C44Mab-3 for Multiple Applications against Pancreatic Carcinomas2023

    • Author(s)
      Kudo Yuma、Suzuki Hiroyuki、Tanaka Tomohiro、Kaneko Mika K.、Kato Yukinari
    • Journal Title

      Antibodies

      Volume: 12 Issue: 2 Pages: 31-31

    • DOI

      10.3390/antib12020031

    • Related Report
      2023 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] A Novel Anti-CD44 Variant 3 Monoclonal Antibody C44Mab-6 Was Established for Multiple Applications2023

    • Author(s)
      Suzuki Hiroyuki、Kitamura Kaishi、Goto Nohara、Ishikawa Kenichiro、Ouchida Tsunenori、Tanaka Tomohiro、Kaneko Mika K.、Kato Yukinari
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 24 Issue: 9 Pages: 8411-8411

    • DOI

      10.3390/ijms24098411

    • Related Report
      2023 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Defucosylated mouse-dog chimeric anti-HER2 monoclonal antibody exerts antitumor activities in mouse xenograft models of canine tumors2022

    • Author(s)
      Suzuki Hiroyuki、Ohishi Tomokazu、Asano Teizo、Tanaka Tomohiro、Saito Masaki、Mizuno Takuya、Yoshikawa Takeo、Kawada Manabu、Kaneko Mika、Kato Yukinari
    • Journal Title

      Oncology Reports

      Volume: 48 Issue: 3 Pages: 154-154

    • DOI

      10.3892/or.2022.8366

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Development of a Novel Anti-CD44 Monoclonal Antibody for Multiple Applications against Esophageal Squamous Cell Carcinomas2022

    • Author(s)
      Goto Nohara、Suzuki Hiroyuki、Tanaka Tomohiro、Asano Teizo、Kaneko Mika K.、Kato Yukinari
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 23 Issue: 10 Pages: 5535-5535

    • DOI

      10.3390/ijms23105535

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Antitumor Activity of an Anti-EGFR/HER2 Bispecific Antibody in a Mouse Xenograft Model of Canine Osteosarcoma2022

    • Author(s)
      Tateyama Nami、Suzuki Hiroyuki、Ohishi Tomokazu、Asano Teizo、Tanaka Tomohiro、Mizuno Takuya、Yoshikawa Takeo、Kawada Manabu、Kaneko Mika K.、Kato Yukinari
    • Journal Title

      Pharmaceutics

      Volume: 14 Issue: 11 Pages: 2494-2494

    • DOI

      10.3390/pharmaceutics14112494

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Role of THG-1 in inflammatory responses of squamous cell carcinoma2023

    • Author(s)
      Yasuhito Okano, Hiroyuki Suzuki, Yukihide Watanabe, Mohammed Abdelaziz, Lev Manevich, Kunio Kawanishi, Shin Matsumoto, Nohara Goto, Ling Zheng, Yukari Okita, Masahiro Nakayama, Yoshihide Shima, Keiji Tabuchi, and Mitsuyasu Kato
    • Organizer
      TGF-beta meeting, Uppsala
    • Related Report
      2023 Research-status Report
    • Int'l Joint Research
  • [Presentation] Regulation of CD44 splicing by THG-1 / TSC22D42022

    • Author(s)
      後藤のはら、鈴木裕之、加藤光保
    • Organizer
      第81回日本癌学会学術総会
    • Related Report
      2022 Research-status Report
  • [Presentation] Development of a Novel Anti-CD44 Monoclonal Antibody for Esophageal Squamous Cell Carcinomas2022

    • Author(s)
      鈴木裕之、後藤のはら、田中智大、金子美華、加藤幸成
    • Organizer
      第81回日本癌学会学術総会
    • Related Report
      2022 Research-status Report
  • [Presentation] Defucosylated Mouse-Dog Chimeric Anti-EGFR Antibody Exerts Antitumor Activities in Mouse Xenograft Models of Canine Tumors2022

    • Author(s)
      鈴木裕之、李冠傑、浅野禎三、田中智大、金子美華、加藤幸成
    • Organizer
      第96回日本薬理学会年会・第43回日本臨床薬理学会学術総会
    • Related Report
      2022 Research-status Report

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Published: 2022-04-19   Modified: 2024-12-25  

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