Cluster microRNAs miR-194 and miR-215 suppress the tumorigenicity of intestinal tumor organoids.
Cluster microRNAs miR-194 and miR-215 suppress the tumorigenicity of intestinal tumor organoids.
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DOI：
10.1111/cas.13165
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发表时间：
2017-04
期刊：
影响因子：
5.7
通讯作者：
Saito H
中科院分区：
文献类型：
--
作者：
Nakaoka T;Saito Y;Shimamoto Y;Muramatsu T;Kimura M;Kanai Y;Saito H
肿瘤干细胞具有自我更新和多潜能，在肿瘤的发生和发展中起着关键作用。最近，一种被称为类器官培养的新的三维培养系统已经开发出来，允许Lgr5阳性的干细胞形成类似于原始组织特性的类器官。在此，我们建立了APC min/+小鼠肠道肿瘤组织和C57BL/6J小鼠正常肠上皮细胞来源的有机体，并研究了microRNA(MiRNA)在肠道肿瘤有机体中的作用。基因芯片分析结果表明，与正常肠上皮来源的器官相比，肠肿瘤组织中的miRNAs簇、miR-194和miR-215的表达明显受到抑制。MiR-194的增强表达导致E2f3的抑制，E2f3是细胞周期的正调控因子，并抑制肠道肿瘤器官的生长。此外，miR-215的强制表达通过下调包括Lgr5在内的肠道干细胞标记物来抑制癌症干细胞签名。这些结果表明，包括miR-194和miR-215在内的miRNA簇在抑制肠道肿瘤器官的生长和减弱茎的形成方面发挥了重要作用。
Tumor stem cells with self‐renewal and multipotent capacity play critical roles in the initiation and progression of cancer. Recently, a new 3‐D culture system known as organoid culture has been developed, allowing Lgr5‐positive stem cells to form organoids that resemble the properties of original tissues. Here we established organoids derived from intestinal tumors of Apc min/+ mice and normal intestinal epithelia of C57BL/6J mice and investigated the roles of microRNA (miRNA) in intestinal tumor organoids. The results of microarray analyses revealed that expression of the cluster miRNAs, miR‐194 and miR‐215 was markedly suppressed in intestinal tumor organoids in comparison with organoids derived from normal intestinal epithelia. Enforced expression of miR‐194 resulted in inhibition of E2f3, a positive regulator of the cell cycle and growth suppression of intestinal tumor organoids. In addition, enforced expression of miR‐215 suppressed the cancer stem cell signature through downregulation of intestinal stem cell markers including Lgr5. These findings indicate that the miRNA cluster including miR‐194 and miR‐215 plays important roles in suppressing the growth and attenuating the stemness of intestinal tumor organoids.