miR-137 Regulates the Tumorigenicity of Colon Cancer Stem Cells through the Inhibition of DCLK1
miR-137 Regulates the Tumorigenicity of Colon Cancer Stem Cells through the Inhibition of DCLK1
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DOI：
10.1158/1541-7786.mcr-15-0380
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发表时间：
2016-04-01
影响因子：
5.2
通讯作者：
Sakai, Yoshiharu
中科院分区：
文献类型：
--
作者：
Sakaguchi, Masazumi;Hisamori, Shigeo;Sakai, Yoshiharu
mirna在调节癌症干细胞（CSC）特性方面具有重要作用，被认为是潜在的治疗靶点。然而，很少有研究关注与结肠CSCs特异性相关的mirna。在这里，基于pcr的正常结肠干细胞（NCSC）和结肠CSC (EpCAM(+)/CD44（+)/CD66a(-)）的miRNA分析鉴定了调节结肠CSC特性的miRNA。有趣的是，与NCSCs相比，miRNA-137 （miR-137）在结肠CSCs中的表达下调，而双皮质素样激酶1 (DCLK1) mRNA在结肠CSCs中高表达，而在NCSCs中低表达。事实上，dclk1阳性的癌细胞在临床切除的结肠癌标本中广泛分布，而dclk1阳性的上皮细胞在包括隐窝底在内的正常结肠组织中很少检测到。荧光素酶分析和免疫印迹分析显示miR-137调节DCLK1基因的表达。外源性miR-137的转导在体外抑制结肠癌类器官的发育和体内结肠癌细胞的致瘤性，而不影响正常肠道类器官的生长。此外，miR-137的抑制增强了正常结肠细胞的类器官发育。这些数据表明，miR-137具有抑制结肠CSCs致瘤性的能力，并且维持miR-137在NCSCs中的表达有助于通过抑制DCLK1表达来抑制不受控制的细胞增殖。结论：miR-137/DCLK1轴在NCSCs和结肠CSCs中是一个重要的调节因子；对这一轴的进一步了解可能会促进针对结肠csc的潜在基因治疗策略的发展。(c) 2016年aacr。
miRNAs have important roles in regulating cancer stem cell (CSC) properties and are considered to be potential therapeutic targets. However, few studies have focused on miRNAs which are specifically related to colon CSCs. Here, a PCR-based miRNA profiling analysis of normal colon stem cells (NCSC) and colon CSCs (EpCAM(+)/CD44(+)/CD66a(-)) identified miRNAs which regulate colon CSC properties. Interestingly, miRNA-137 (miR-137) expression was downregulated in the colon CSCs compared with NCSCs, while doublecortin-like kinase 1 (DCLK1) mRNA was highly expressed in the colon CSCs but low in the NCSCs. In fact, DCLK1-positive cancer cells were widely distributed in clinically resected colon cancer specimens, while DCLK1-positve epithelial cells were rarely detected in normal colon tissues including the crypt bottoms. Luciferase assay and immunoblot analysis revealed that miR-137 regulated DCLK1 gene expression. Transduction of exogenous miR-137 suppressed the development of colon cancer organoids in vitro and the tumorigenicity of colon cancer cells in vivo without affecting the growth of normal intestinal organoids. Furthermore, the suppression of miR-137 enhanced the organoid development of normal colon cells. These data demonstrate that miR-137 has the capacity to suppress the tumorigenicity of colon CSCs and that maintained expression of miR-137 in NCSCs contributes to suppressing uncontrolled cell proliferation through the inhibition of DCLK1 expression.Implications: The miR-137/DCLK1 axis as an important regulator in NCSCs and colon CSCs; further understanding of this axis may foster the development of potential gene therapeutic strategies targeting colon CSCs. (C) 2016 AACR.