Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Maidashi3-1-1, Fukuoka, 812-8582, Japan.
Cancer Cell Int. 2013 Mar 4;13(1):21. doi: 10.1186/1475-2867-13-21.
Diverse functions of microRNAs (miRNAs), including effects on tumorigenesis, proliferation, and differentiation, have been reported, and several miRNAs have also been demonstrated to play an important role in apoptosis. In this study, we investigated the possible role that miRNAs may play in the development of chemoresistance in Ewing sarcoma/primitive neuroectodermal tumor (EWS).
We screened doxorubicin (Dox)-resistant EWS cells to identify any distinct miRNA sequences that may regulate the chemoresistance of EWS cells. The effects of miRNAs were evaluated using a chemosensitivity assay. The possible target genes of the miRNAs were predicted using a web-based prediction program.
We found miR-125b to be upregulated in two different Dox-resistant EWS cell lines. The upregulation of miR-125b was also confirmed in the EWS tumors having survived chemotherapy regimen which includes doxorubicin. When miR-125b was knocked down in EWS cells, both the Dox-resistant and parental cells showed an enhanced sensitivity to doxorubicin, which was associated with the upregulation of the pro-apoptotic molecules, p53 and Bak. Inversely, the overexpression of miR-125b in parental EWS cells resulted in enhanced drug resistance, not only to doxorubicin, but also to etoposide and vincristine.
Our findings suggest that miR-125b may play a role in the development of chemoresistance in EWS by suppressing the expression of the apoptotic mediators, such as p53 and Bak.
微小 RNA（miRNA）具有多种功能，包括对肿瘤发生、增殖和分化的影响，并且已经证实几种 miRNA 在细胞凋亡中发挥着重要作用。在本研究中，我们研究了 miRNA 在尤文肉瘤/原始神经外胚层肿瘤（EWS）化疗耐药中的可能作用。
我们筛选多柔比星（Dox）耐药的 EWS 细胞，以鉴定可能调节 EWS 细胞化疗耐药性的独特 miRNA 序列。使用化疗敏感性测定评估 miRNA 的作用。使用基于网络的预测程序预测 miRNA 的可能靶基因。
我们发现两种不同的 Dox 耐药 EWS 细胞系中 miR-125b 上调。在包括多柔比星在内的化疗方案存活的 EWS 肿瘤中也证实了 miR-125b 的上调。当 miR-125b 在 EWS 细胞中被敲低时，耐药和亲本细胞对多柔比星的敏感性均增强，这与促凋亡分子 p53 和 Bak 的上调有关。相反，miR-125b 在亲本 EWS 细胞中的过表达导致对多柔比星、依托泊苷和长春新碱的耐药性增强。
我们的研究结果表明，miR-125b 通过抑制凋亡介质（如 p53 和 Bak）的表达，在 EWS 化疗耐药的发展中发挥作用。
