| Project/Area Number |
22K06995
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Review Section |
Basic Section 49030:Experimental pathology-related
|
|---|
| 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
|
| 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)
|
|---|
| Keywords | THG-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。
|
