The association between let-7, RAS and HIF-1α in Ewing Sarcoma tumor growth
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Michal Hameiri-Grossman1,7,*, Adi Porat-Klein1,7,*, Isaac Yaniv1,2,7, Shifra Ash2,7, Ian J. Cohen2,7, Yona Kodman2, Ronit Haklai 3, Galit Elad-Sfadia3, Yoel Kloog3, Elena Chepurko1, Meora Feinmesser4,7, Josephine Issakov5,7, Osnat Sher5,7, Drorit Luria2, Yehuda Kollender6,7, Avraham Weizman1,7 and Smadar Avigad1,2,7
1 Molecular Oncology, Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, Israel
2 Pediatric Hematology Oncology, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel
3 Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
4 Pathology Department, Rabin Medical Center, Petah Tikva, Israel
5 Pathology Department, Sourasky Medical Center, Tel Aviv, Israel
6 Unit of Orthopedic Oncology, Sourasky Medical Center, Tel Aviv, Israel
7 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
* These authors have contributed equally to this work
Smadar Avigad, email:
Keywords: microRNA, let-7, RAS, Ewing sarcoma, HIF-1α
Received: February 26, 2015 Accepted: August 23, 2015 Published: September 10, 2015
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.
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