Growth-promoting role of the miR-106a~363 cluster in Ewing sarcoma.
Growth-promoting role of the miR-106a~363 cluster in Ewing sarcoma.
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DOI：
10.1371/journal.pone.0063032
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Jedlicka P
中科院分区：
文献类型：
--
作者：
Dylla L;Jedlicka P
microRNA（miRs）已被鉴定为正常发育和癌症标志的有效调节剂。靶向microRNA已被证明具有临床前前景，并且选择的基于miR的疗法现在处于临床试验中。尤因肉瘤是一种生物学侵袭性儿科癌症，尽管化疗方案有所改进，但临床结局变化不大。目前迫切需要新的治疗方法来改善尤文肉瘤的预后并预防化疗相关的继发性后遗症。大多数尤文肉瘤肿瘤是由EWS/Fli-1融合癌蛋白驱动的，作为一种功能获得性转录因子，引起多种靶点（包括microRNA）的失调。我们以前的研究和其他人的研究已经确定了尤文肉瘤中属于相关miR-17 β 92 a、miR-106 b β 25和miR-106 a β 363簇的miR的上调。然而，其功能后果尚未得到表征，也没有探索将miR阻断作为尤因肉瘤的抗癌策略。为了模拟潜在的治疗方法，我们检查了阻断这些簇及其组分miR的效果。使用集落形成作为读数，我们发现使用特异性抑制剂阻断所选的单个簇组分miR几乎没有或没有效果。另一方面，使用miR“海绵”方法的组合抑制抑制对集落形成具有抑制作用，其中阻断整个簇通常比阻断miR家族更有效。我们表明，miR-106 a-363簇的miR-阻断海绵是尤文肉瘤细胞系亚群中克隆形成生长的特别有效的抑制剂。我们进一步确定了miR-15 a的上调作为促进miR-106 a对海绵生长抑制作用的下游机制。综上所述，我们的研究为miR-106 a β 363簇在尤文肉瘤中的促癌作用提供了支持，并确定了miR-106 a β 363阻断以及miR-15 a替代作为抑制尤文肉瘤生长的可能策略。
MicroRNAs (miRs) have been identified as potent regulators of both normal development and the hallmarks of cancer. Targeting of microRNAs has been shown to have preclinical promise, and select miR-based therapies are now in clinical trials. Ewing Sarcoma is a biologically aggressive pediatric cancer with little change in clinical outcomes despite improved chemotherapeutic regimens. There is a substantial need for new therapies to improve Ewing Sarcoma outcomes and to prevent chemotherapy-related secondary sequelae. Most Ewing Sarcoma tumors are driven by the EWS/Fli-1 fusion oncoprotein, acting as a gain-of-function transcription factor causing dysregulation of a variety of targets, including microRNAs. Our previous studies, and those of others, have identified upregulation of miRs belonging to the related miR-17∼92a, miR-106b∼25, and miR-106a∼363 clusters in Ewing Sarcoma. However, the functional consequences of this have not been characterized, nor has miR blockade been explored as an anti-cancer strategy in Ewing Sarcoma. To simulate a potential therapeutic approach, we examined the effects of blockade of these clusters, and their component miRs. Using colony formation as a read-out, we find that blockade of selected individual cluster component miRs, using specific inhibitors, has little or no effect. Combinatorial inhibition using miR “sponge” methodology, on the other hand, is inhibitory to colony formation, with blockade of whole clusters generally more effective than blockade of miR families. We show that a miR-blocking sponge directed against the poorly characterized miR-106a∼363 cluster is a particularly potent inhibitor of clonogenic growth in a subset of Ewing Sarcoma cell lines. We further identify upregulation of miR-15a as a downstream mechanism contributing to the miR-106a∼363 sponge growth-inhibitory effect. Taken together, our studies provide support for a pro-oncogenic role of the miR-106a∼363 cluster in Ewing Sarcoma, and identify miR-106a∼363 blockade, as well as miR-15a replacement, as possible strategies for inhibition of Ewing Sarcoma growth.
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