title: The association between let-7, RAS and HIF-1α in Ewing Sarcoma tumor growth.
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.
authors.affiliation: Molecular Oncology, Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Hameiri-Grossman
authors.affiliation: Molecular Oncology, Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Adi
authors.initials: A
authors.lastname: Porat-Klein
authors.affiliation: Molecular Oncology, Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, Israel.|Pediatric Hematology Oncology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Isaac
authors.initials: I
authors.lastname: Yaniv
authors.affiliation: Pediatric Hematology Oncology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Shifra
authors.initials: S
authors.lastname: Ash
authors.affiliation: Pediatric Hematology Oncology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Cohen
authors.affiliation: Pediatric Hematology Oncology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.
authors.forename: Yona
authors.initials: Y
authors.lastname: Kodman
authors.affiliation: Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ronit
authors.initials: R
authors.lastname: Haklai
authors.affiliation: Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Galit
authors.initials: G
authors.lastname: Elad-Sfadia
authors.affiliation: Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Yoel
authors.initials: Y
authors.lastname: Kloog
authors.affiliation: Molecular Oncology, Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, Israel.
authors.forename: Elena
authors.initials: E
authors.lastname: Chepurko
authors.affiliation: Pathology Department, Rabin Medical Center, Petah Tikva, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Meora
authors.initials: M
authors.lastname: Feinmesser
authors.affiliation: Pathology Department, Sourasky Medical Center, Tel Aviv, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Josephine
authors.initials: J
authors.lastname: Issakov
authors.affiliation: Pathology Department, Sourasky Medical Center, Tel Aviv, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Osnat
authors.initials: O
authors.lastname: Sher
authors.affiliation: Pediatric Hematology Oncology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.
authors.forename: Drorit
authors.initials: D
authors.lastname: Luria
authors.affiliation: Unit of Orthopedic Oncology, Sourasky Medical Center, Tel Aviv, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Kollender
authors.affiliation: Molecular Oncology, Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Avraham
authors.initials: A
authors.lastname: Weizman
authors.affiliation: Molecular Oncology, Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, Israel.|Pediatric Hematology Oncology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Smadar
authors.initials: S
authors.lastname: Avigad
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002453:Cell Cycle; D002465:Cell Movement; D002470:Cell Survival; D002648:Child; D002675:Child, Preschool; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D018572:Disease-Free Survival; D005204:Farnesol / Q000031:analogs & derivatives / Q000627:therapeutic use; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007223:Infant; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000378:metabolism*; D009368:Neoplasm Transplantation; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D051789:Proto-Oncogene Protein c-fli-1 / Q000378:metabolism; D034802:RNA-Binding Protein EWS / Q000378:metabolism; D011897:Random Allocation; D012459:Salicylates / Q000627:therapeutic use; D012512:Sarcoma, Ewing / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D055815:Young Adult; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C106031:EWS-FLI fusion protein; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D035683:MicroRNAs; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D012459:Salicylates; C093323:farnesylthiosalicylic acid; C487931:mirnlet7 microRNA, human; D005204:Farnesol; D018631:ras Proteins
keywords: Ewing sarcoma; HIF-1α; RAS; let-7; microRNA