Development of novel treatments for colorectal cancer focusing on Lgr5 splicing variants

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08678
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Osaka University
• Principal Investigator: Takahashi Hidekazu 大阪大学, 医学系研究科, 助教 (10528508)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 進行再発大腸癌 / 抗がん剤耐性 / COX-2阻害剤

Outline of Final Research Achievements

As a result of comprehensive analysis of gene expression by suppressing Syntenin-1 using colorectal cancer cell lines SW480, SW620, and HT29, changes in prostaglandin signal were observed. This was the same as the behavior when COX2 was inhibited. This suggests that Syntenin-1 is involved in the COX-2 signal. LGR5 is said to control stem cell nature, but inhibition of Syntenin-1 reduced anticancer drug resistance to support this stem cell nature. When used in combination with a COX-2 inhibitor to increase the sensitivity of chemotherapy, a significant synergistic effect was observed. The possibility as a useful combination therapy was suggested.

Free Research Field

消化器外科学

Academic Significance and Societal Importance of the Research Achievements

癌幹細胞表面分子である全長型LGR5、LGR5スプライシングバリアントの意義を解明すべく遺伝子ではなく、タンパク質の網羅的解析を行った。結果Syntenin-1が同定された。Syntenin-1はCOX-2シグナルの伝達に重要な役割を果たしており抗がん剤耐性に寄与した。
この事実を臨床応用するに際し、現在施行されている化学療法の感受性を増強させるためにCOX-2阻害剤との併用を行ったところ、著明な相乗効果を認めた。現状の化学療法もCOX-2阻害剤も臨床応用が可能なため、COX-2阻害剤が抗がん剤としてのドラッグリポジショニングとしての可能性が示唆された。