Development of a novel nucleic acid medicine targeting cancer stem-related marker Dclk1

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K16361
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Osaka University
• Principal Investigator: Tsujimura Naoto 大阪大学, 医学部附属病院, 医員 (10804198)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Keywords: microRNA / colorectal cancer / miR-1291 / cancer stemness

Outline of Final Research Achievements

Cancer stem cells (CSCs) are drug-tolerant and cause distant metastasis and recurrence in various cancers. Thus, CSC-targeted therapy may be an effective curative approach in CRC. In this study, we identified miR-1291 after screening of DCLK-1(doublecortin-like kinase 1) binding ability as a possible nucleic acid medicine against CSCs. MiR-1291 significantly suppressed the proliferation, invasion, migration, and colony formation capability of colon cancer cell lines. MiR-1291 caused altered expression of the cell cycle-regulatory proteins such as CDK inhibitors p21WAF1/CIP1 and p27KIP1, CDK4, CDK6, and cyclin E1, and CDC25A. We found that miR-1291 directly bound the 3’ UTR sequence of DCLK-1 and suppressed its expression at both the mRNA and protein levels. Moreover, miR-1291 suppressed CSC markers Bmi1 and CD133. Our data suggest that miR-1291 has an anti-tumor effect by modulating multiple functions, including invasiveness, cell cycle, and cancer stemness.

Free Research Field

消化器外科、大腸癌

Academic Significance and Societal Importance of the Research Achievements

核酸医薬による癌治療や癌幹細胞標的治療の開発は非常に有望な医学分野であり、世界規模で研究開発競争が展開されている。癌幹細胞を標的とした核酸医薬の開発は癌幹細胞が集団内に僅かしか存在せず、効果を評価することが困難であることから開発が遅れているが、私たちは、独自に開発した癌幹細胞濃縮法を用いて癌幹細胞を死滅させるmiRNAのスクリーニングを行い、消化管幹細胞マーカーの候補遺伝子であるDclk1を標的とした癌幹細胞に効果を示す新しい核酸医薬 (miR-1291) の同定に成功した。