Abstract
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.
Highlights
Ewing Sarcoma (ES) is the second most common primary malignant bone tumor in children and adolescents [1]
We were interested in miRNAs located on chromosomes 11 and 22 that are involved in the most prevalent translocation in ES resulting in the chimeric transcript EWS-FLI-1
Our aim in this work was to reveal potential pathways that contribute to the aggressiveness of ES, through microRNA analysis. miRNAs have been shown to be located at fragile sites and at cancer associated regions [19]
Summary
Ewing Sarcoma (ES) is the second most common primary malignant bone tumor in children and adolescents [1]. ES is characterized by specific translocations fusing the EWS gene with different members of the ETS transcription family, the most frequent is the EWS-FLI-1 fusion [2, 3]. MiRNAs have been shown to be involved in many cellular processes, including in cancer as tumor suppressors or oncogenes [5]. One of the most studied miRNA is let-7. The human let-7 family consists of 13 genes, is highly conserved and has been found to be downregulated in several malignancies such as lung cancer, colon, breast, and acute lymphoblastic leukemia [6]. One of the validated targets of let-7 is the RAS oncogene [7]
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