2019 Fiscal Year Final Research Report
Functional analysis of novel cancer-related gene of HCC identified by RNAi screening method
| Project/Area Number |
16K09357
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Research Field |
Gastroenterology
|
|---|
| Research Institution | Kyoto University |
|---|
Principal Investigator |
Takai Atsushi 京都大学, 医学研究科, 特定助教 (80760587)
|
|---|
| Project Period (FY) |
2016-04-01 – 2020-03-31
|
| Keywords | 肝癌 / 癌幹細胞 / EpCAM / PMPCB |
|---|
| Outline of Final Research Achievements |
We characterized PMPCB gene, which plays a role in mitochondrial protein processing, as a bona fide target for Epcam positive HCC. PMPCB blocking suppressed EpCAM expression and induced apoptosis specifically in EpCAM positive liver cancer cells in vitro and in vivo. PMPCB inhibition decreased the activity of Wnt/beta-catenin signaling via mitochondria-related reactive oxygen species production and FOXO activities, resulting in apoptosis and tumor suprression. These results indicate that a synthetic lethality screen is a viable strategy to identify actionable drivers of HCC and identify PMPCB as a therapeutically vulnerable gene in EpCAM positive HCC supopulations.
|
| Free Research Field |
消化器内科学
|
| Academic Significance and Societal Importance of the Research Achievements |
本研究では、肝癌の幹/前駆細胞を標的とした治療の開発に当たり、肝癌幹/前駆細胞のマーカーであるEpCAMと、global RNAiスクリーニングでEpCAMとsynthetic lethalな関係性を持つ候補分子としてミトコンドリアプロセシングタンパクであるPMPCBに着目し、機能解析を行った。その結果、PMPCBの機能を阻害することで、beta-catenin pathwayの活性を低下させ、EpCAM陽性肝癌細胞のみを選択的にアポトーシスに誘導できることが分かった。本研究成果は、癌幹/前駆細胞を標的とした新しい治療法の開発につながり、今後の肝癌診療の発展に大きく寄与することが期待される。
|
