miR-137 Regulates the Tumorigenicity of Colon Cancer Stem Cells through the Inhibition of DCLK1

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K10539
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Kyoto University
• Principal Investigator: Hisamori Shigeo 京都大学, 医学研究科, 助教 (50534351)
• Research Collaborator: Sakaguchi Masazumi 京都大学大学院医学研究科, 消化管外科, 大学院生 ; Shimono Yohei 藤田医科大学医学部, 生化学講座, 教授
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 大腸癌 / マイクロRNA / 大腸癌幹細胞 / 正常大腸幹細胞

Outline of Final Research Achievements

DCLK1-positive colon cancer cells were widely distributed in the colon cancer specimens, while DCLK1-positive epithelial cells were rarely detected in normal colon tissues, including the crypt bottoms. MiRNA-137(miR-137) was highly expressed in the NCoSC population, whereas the DCLK1 mRNA expression was significantly upregulated in the CoCSC population. The defect in organoid development by the transduction of miR-137 and shRNAs were substantially rescued by co-expression of the exogenous DCLK1. Although miRNA-137 overexpression did not affect the organoid development of the normal intestine, miRNA-137 knockdown promoted the organoid development of normal colon cells. miR-137 has the potential function to suppress the tumorigenicity of CoCSCs and that maintained expression of miR-137 in NCoSCs contributes to suppress uncontrolled cell proliferation through the inhibition of DCLK1 expression.

Free Research Field

消化器外科

Academic Significance and Societal Importance of the Research Achievements

正常大腸幹細胞(NCoSCs)と大腸癌幹細胞(CoCSCs)は、組織再形成・細胞増殖のため共通のメカニズムを有していると考えられている。近年マウスを用いた研究で、DCLK1が、正常大腸には発現せず、小腸腺腫の幹細胞にのみ発現していることが報告されたが、ヒトCoCSCsとDCLK1の発現については詳細な研究は進んでいなかった。
今回の我々の研究結果から、miR-137はDCLK1発現を制御することでCoCSCsの腫瘍形成能を抑制することが示唆された。本結果から正常大腸組織を障害せずCoCSCsを標的とした新規治療戦略を提示できる可能性があると考える。