Neural Stem Cell Biology Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.
Stem Cells. 2015 May;33(5):1377-89. doi: 10.1002/stem.1958.
microRNAs (miRNAs) are short noncoding RNAs, which regulate gene expression post-transcriptionally and play crucial roles in relevant biological and pathological processes. Here, we investigated the putative role of miRNAs in modulating the tumor-initiating potential of mouse medulloblastoma (MB)-derived cancer stem cells (CSCs). We first subjected bona fide highly tumorigenic (HT) CSCs as well as lowly tumorigenic MB CSCs and normal neural stem cells to miRNA profiling, which identified a HT CSC-specific miRNA signature. Next, by cross-checking CSC mRNA/miRNA profiles, we pinpointed miR-135a as a potential tumor suppressor gene, which was strongly downregulated in HT CSCs as well as in the highly malignant experimental tumors derived from them. Remarkably, enforced expression of miR-135a in HT CSCs strongly inhibited tumorigenesis by repressing the miR-135a direct target gene Arhgef6. Considering the upregulation of Arhgef6 in human MBs and its involvement in mediating experimental medulloblastomagenesis, its efficient suppression by miR-135a might make available an effective therapeutic strategy to selectively impair the tumorigenic potential of MB CSCs. Stem Cells 2015;33:1377-1389.
微小 RNA（miRNAs）是短的非编码 RNA，可在后转录水平上调节基因表达，并在相关的生物学和病理学过程中发挥关键作用。在这里，我们研究了 miRNAs 在调节小鼠髓母细胞瘤（MB）衍生的肿瘤起始细胞（CSC）的肿瘤起始潜能中的可能作用。我们首先对真正的高致瘤性（HT）CSC 以及低致瘤性 MB CSC 和正常神经干细胞进行 miRNA 谱分析，鉴定出 HT CSC 特异性 miRNA 特征。接下来，通过交叉检查 CSC mRNA/miRNA 谱，我们确定 miR-135a 是一种潜在的肿瘤抑制基因，它在 HT CSC 以及源自它们的高度恶性实验肿瘤中强烈下调。值得注意的是，在 HT CSC 中强制表达 miR-135a 通过抑制 miR-135a 的直接靶基因 Arhgef6 强烈抑制肿瘤发生。鉴于 Arhgef6 在人类 MB 中的上调及其在介导实验性髓母细胞瘤发生中的作用，miR-135a 的有效抑制可能为选择性损害 MB CSC 的肿瘤发生潜能提供有效的治疗策略。干细胞 2015;33:1377-1389。
