The association between let-7, RAS and HIF-1α in Ewing Sarcoma tumor growth.
The association between let-7, RAS and HIF-1α in Ewing Sarcoma tumor growth.
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Ewing肉瘤肿瘤生长中Let-7，Ras和HIF-1α之间的关联。
DOI：
10.18632/oncotarget.5616
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发表时间：
2015-10-20
期刊：
影响因子：
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通讯作者：
Avigad S
中科院分区：
文献类型：
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作者：
Hameiri-Grossman M;Porat-Klein A;Yaniv I;Ash S;Cohen IJ;Kodman Y;Haklai R;Elad-Sfadia G;Kloog Y;Chepurko E;Feinmesser M;Issakov J;Sher O;Luria D;Kollender Y;Weizman A;Avigad S
尤文肉瘤（ES）是儿童和青少年中第二常见的原发性恶性骨肿瘤。microRNA（miRNAs）作为肿瘤抑制因子或癌基因参与癌症。我们研究了位于染色体11 q和22 q上的miRNAs参与ES中最常见的易位。其中，我们重点关注了属于let-7家族的3种。我们研究了let-7a和let-7 b的表达水平，发现let-7 b的低表达与复发风险增加之间存在显著相关性。已知let-7是RAS癌基因的负调节因子。事实上，我们检测到let-7的表达和RAS蛋白水平与其下游靶点p-ERK之间的负相关，转染let-7模拟物和抑制剂。此外，我们确定let-7是HIF-1α和EWS-FLI-1的负调节因子。此外，我们能够证明HIF-1α直接与EWS-FLI-1启动子结合。Salirasib体外处理导致细胞活力、迁移能力的降低和S期细胞的减少。治疗后，在小鼠中观察到肿瘤负荷以及HIF-1α和EWS-FLI-1蛋白的表达水平显著降低。我们的研究结果支持let-7是一种负调节RAS的肿瘤抑制因子的假设，同样在ES中，HIF-1α可能有助于ES的侵袭性转移行为。此外，Salirasib治疗后ES小鼠模型中肿瘤负荷的降低表明这种RAS抑制剂在ES中的治疗潜力。
Ewing Sarcoma (ES) is the second most common primary malignant bone tumor in children and adolescents. microRNAs (miRNAs) are involved in cancer as tumor suppressors or oncogenes. We studied the involvement of miRNAs located on chromosomes 11q and 22q that participate in the most common translocation in ES. Of these, we focused on 3 that belong to the let-7 family. We studied the expression levels of let-7a, and let-7b and detected a significant correlation between low expression of let-7b and increased risk of relapse. let-7 is known to be a negative regulator of the RAS oncogene. Indeed, we detected an inverse association between the expression of let-7 and RAS protein levels and its downstream target p-ERK, following transfection of let-7 mimics and inhibitors. Furthermore, we identified let-7 as a negative regulator of HIF-1α and EWS-FLI-1. Moreover, we were able to show that HIF-1α directly binds to the EWS-FLI-1 promoter. Salirasib treatment in-vitro resulted in the reduction of cell viability, migration ability, and in the decrease of cells in S-phase. A significant reduction in tumor burden and in the expression levels of both HIF-1α and EWS-FLI-1 proteins were observed in mice after treatment. Our results support the hypothesis that let-7 is a tumor suppressor that negatively regulates RAS, also in ES, and that HIF-1α may contribute to the aggressive metastatic behavior of ES. Moreover, the reduction in the tumor burden in a mouse model of ES following Salirasib treatment, suggests therapeutic potential for this RAS inhibitor in ES.