1] Rutgers University-Graduate School of Biomedical Science, Newark, New Jersey, USA [2] New Jersey Medical School, Newark, New Jersey, USA.
Mol Ther Nucleic Acids. 2013 Oct 1;2(10):e126. doi: 10.1038/mtna.2013.60.
Glioblastoma multiforme (GBM), the most common and lethal tumor of the adult brain, generally shows chemo- and radioresistance. MicroRNAs (miRs) regulate physiological processes, such as resistance of GBM cells to temozolomide (TMZ). Although miRs are attractive targets for cancer therapeutics, the effectiveness of this approach requires targeted delivery. Mesenchymal stem cells (MSCs) can migrate to the sites of cancers, including GBM. We report on an increase in miR-9 in TMZ-resistant GBM cells. miR-9 was involved in the expression of the drug efflux transporter, P-glycoprotein. To block miR-9, methods were developed with Cy5-tagged anti-miR-9. Dye-transfer studies indicated intracellular communication between GBM cells and MSCs. This occurred by gap junctional intercellular communication and the release of microvesicles. In both cases, anti-miR-9 was transferred from MSCs to GBM cells. However, the major form of transfer occurred with the microvesicles. The delivery of anti-miR-9 to the resistant GBM cells reversed the expression of the multidrug transporter and sensitized the GBM cells to TMZ, as shown by increased cell death and caspase activity. The data showed a potential role for MSCs in the functional delivery of synthetic anti-miR-9 to reverse the chemoresistance of GBM cells.Molecular Therapy-Nucleic Acids (2013) 2, e126; doi:10.1038/mtna.2013.60; published online 1 October 2013.
多形性胶质母细胞瘤（GBM）是成人脑内最常见和最致命的肿瘤，通常表现出对化疗和放疗的抗性。microRNAs（miRs）调节生理过程，如GBM 细胞对替莫唑胺（TMZ）的抗性。虽然 miRs 是癌症治疗的有吸引力的靶点，但这种方法的有效性需要靶向递送。间充质干细胞（MSCs）可以迁移到包括 GBM 在内的癌症部位。我们报告 TMZ 耐药的 GBM 细胞中 miR-9 的增加。miR-9 参与了药物外排转运蛋白 P-糖蛋白的表达。为了阻断 miR-9，开发了用 Cy5 标记的抗 miR-9 方法。染料转移研究表明 GBM 细胞和 MSCs 之间存在细胞内通讯。这是通过间隙连接细胞间通讯和微泡的释放来实现的。在这两种情况下，抗 miR-9 都从 MSCs 转移到 GBM 细胞。然而，主要的转移形式是通过微泡进行的。向耐药 GBM 细胞递送抗 miR-9 逆转了多药转运蛋白的表达，并使 GBM 细胞对 TMZ 敏感，如细胞死亡和半胱天冬酶活性增加所示。数据显示，MSCs 在功能性递送合成抗 miR-9 以逆转 GBM 细胞的化疗耐药性方面可能发挥作用。分子治疗-核酸（2013）2，e126；doi:10.1038/mtna.2013.60；在线发表于 2013 年 10 月 1 日。
