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

2023 Fiscal Year Research-status Report

• Project/Area Number: 22K06995
• Research Institution: Tohoku 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
• Keywords: THG-1 / TSC22D4 / Interleukin-1 / TRAF6 / NRBP1 / Squamous cell carcinoma

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

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。

Causes of Carryover

現在投稿中の論文掲載費に充当するため。

Research Products

• [Journal Article] Promotion of squamous cell carcinoma tumorigenesis by oncogene‐mediated THG‐1/TSC22D4 phosphorylation (2023)
  • Author(s): Goto Nohara、Suzuki Hiroyuki、Zheng Ling、Okano Yasuhito、Okita Yukari、Watanabe Yukihide、Kato Yukinari、Kato Mitsuyasu
  • Journal Title: Cancer Science Volume: 114 Pages: 3972～3983
  • DOI: 10.1111/cas.15934
  • Peer Reviewed / Open Access
• [Journal Article] Development of a Novel Anti-CD44 Variant 5 Monoclonal Antibody C44Mab-3 for Multiple Applications against Pancreatic Carcinomas (2023)
  • Author(s): Kudo Yuma、Suzuki Hiroyuki、Tanaka Tomohiro、Kaneko Mika K.、Kato Yukinari
  • Journal Title: Antibodies Volume: 12 Pages: 31～31
  • DOI: 10.3390/antib12020031
  • Peer Reviewed / Open Access
• [Journal Article] A Novel Anti-CD44 Variant 3 Monoclonal Antibody C44Mab-6 Was Established for Multiple Applications (2023)
  • 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 Pages: 8411～8411
  • DOI: 10.3390/ijms24098411
  • Peer Reviewed / Open Access
• [Presentation] Role of THG-1 in inflammatory responses of squamous cell carcinoma (2023)
  • 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
  • Int'l Joint Research