Lee Hae Kyung, Finniss Susan, Cazacu Simona, Bucris Efrat, Ziv-Av Amotz, Xiang Cunli, Bobbitt Kevin, Rempel Sandra A, Hasselbach Laura, Mikkelsen Tom, Slavin Shimon, Brodie Chaya
Davidson Laboratory of Cell Signaling and Tumorigenesis, Hermelin Brain Tumor Center, Department of Neurosurgery, Henry Ford Hospital, Detroit, MI, USA.
Oncotarget. 2013 Feb;4(2):346-61. doi: 10.18632/oncotarget.868.
MicroRNAs (miRNAs) have emerged as potential cancer therapeutics; however, their clinical use is hindered by lack of effective delivery mechanisms to tumor sites. Mesenchymal stem cells (MSCs) have been shown to migrate to experimental glioma and to exert anti-tumor effects by delivering cytotoxic compounds. Here, we examined the ability of MSCs derived from bone marrow, adipose tissue, placenta and umbilical cord to deliver synthetic miRNA mimics to glioma cells and glioma stem cells (GSCs). We examined the delivery of miR-124 and miR-145 mimics as glioma cells and GSCs express very low levels of these miRNAs. Using fluorescently labeled miRNA mimics and in situ hybridization, we demonstrated that all the MSCs examined delivered miR-124 and miR-145 mimics to co-cultured glioma cells and GSCs via gap junction- dependent and independent processes. The delivered miR-124 and miR-145 mimics significantly decreased the luciferase activity of their respected reporter target genes, SCP-1 and Sox2, and decreased the migration of glioma cells and the self-renewal of GSCs. Moreover, MSCs delivered Cy3-miR-124 mimic to glioma xenografts when administered intracranially. These results suggest that MSCs can deliver synthetic exogenous miRNA mimics to glioma cells and GSCs and may provide an efficient route of therapeutic miRNA delivery in vivo.
微小RNA（miRNA）已成为潜在的癌症治疗手段；然而，其临床应用因缺乏有效的肿瘤部位递送机制而受到阻碍。间充质干细胞（MSC）已被证明可迁移至实验性胶质瘤，并通过递送细胞毒性化合物发挥抗肿瘤作用。在此，我们研究了源自骨髓、脂肪组织、胎盘和脐带的MSC将合成的miRNA模拟物递送至胶质瘤细胞和胶质瘤干细胞（GSC）的能力。我们检测了miR-124和miR-145模拟物的递送情况，因为胶质瘤细胞和GSC中这些miRNA的表达水平非常低。使用荧光标记的miRNA模拟物和原位杂交技术，我们证明所有检测的MSC通过依赖和不依赖间隙连接的过程将miR-124和miR-145模拟物递送至共培养的胶质瘤细胞和GSC。递送的miR-124和miR-145模拟物显著降低了其相应报告靶基因SCP-1和Sox2的荧光素酶活性，并降低了胶质瘤细胞的迁移和GSC的自我更新能力。此外，当颅内给药时，MSC将Cy3-miR-124模拟物递送至胶质瘤异种移植瘤。这些结果表明，MSC可将合成的外源性miRNA模拟物递送至胶质瘤细胞和GSC，并可能在体内提供一种有效的治疗性miRNA递送途径。
