| Project/Area Number |
17K15634
|
|---|
| Research Category |
Grant-in-Aid for Young Scientists (B)
|
| Allocation Type | Multi-year Fund |
|---|
| Research Field |
Human pathology
|
|---|
| Research Institution | University of Tsukuba |
|---|
Principal Investigator |
Shiba Aya 筑波大学, 医学医療系, 助教 (50708427)
|
|---|
| Research Collaborator |
Kim Yunjung
|
|---|
| Project Period (FY) |
2017-04-01 – 2019-03-31
|
| Project Status |
Completed (Fiscal Year 2018)
|
| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
|
|---|
| Keywords | 肺腺癌 / 脱ユビキチン化 / 受容体型チロシンキナーゼ / SFN / USP8 / チロシンキナーゼ / リサイクリング / 初期悪性化 |
|---|
| Outline of Final Research Achievements |
Stratifin (SFN, 14-3-3 sigma) acts as a novel oncogene, accelerating the tumor initiation and progression of lung adenocarcinoma. We previously revealed that SFN specifically bound to USP8. Here we showed that both USP8 and SFN showed higher expression in human lung adenocarcinoma than in normal lung tissue, and USP8 expression was significantly correlated with SFN expression. SFN Expression was also associated with poor prognosis. USP8 stabilizes receptor tyrosine kinases (RTKs) such as EGFR and MET by deubiquitination, contributing to the proliferative activity of many human cancers including non-small cell lung cancer. In vitro, USP8 binds to SFN and they co-localize at the early endosomes in lung adenocarcinoma cells. Moreover, USP8 or SFN knockdown leads to downregulation of tumor cellular proliferation and upregulation of apoptosis, p-EGFR or p-MET, which are related to the degradation pathway, and accumulation of ubiquitinated RTKs, leading to lysosomal degradation.
|
| Academic Significance and Societal Importance of the Research Achievements |
USP8阻害剤はEGFR変異の有無に係らず非小細胞肺癌に制癌作用を示すと報告されているが、本研究によりSFNがUSP8に匹敵する治療標的であることが示され、SFNを阻害することで癌細胞のみでRTKsの脱ユビキチン化を抑制する副作用の少ない新規肺腺癌治療薬の開発に繋がると期待される。一方で、SFNを標的とした治療もEGFR変異非依存的な抗腫瘍効果が期待でき、EGFR阻害薬に対する獲得耐性の克服にも貢献できる可能性がある。
|
