The role of miR-17-92 in the miRegulatory landscape of Ewing sarcoma
| Autor: | Schwentner, Raphaela, Herrero-Martin, David, Kauer, Maximilian O, Mutz, Cornelia N, Katschnig, Anna M, Sienski, Grzegorz, Alonso, Javier, Aryee, Dave N T, Kovar, Heinrich |
|---|---|
| Přispěvatelé: | Austrian Science Fund, Unión Europea. Comisión Europea. 7 Programa Marco |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Oncogene Proteins
Fusion Sarcoma Ewing Transforming Growth Factor beta Cell Line Tumor TGFB/BMP pathway Humans Genetic Predisposition to Disease 3' Untranslated Regions EWS-FLI1 Oligonucleotide Array Sequence Analysis Proto-Oncogene Protein c-fli-1 Reverse Transcriptase Polymerase Chain Reaction Sequence Analysis RNA Gene Expression Profiling miR-17-92 PAR-CLIP Gene Expression Regulation Neoplastic MicroRNAs Bone Morphogenetic Proteins Mutation RNA Long Noncoding RNA-Binding Protein EWS Ewing sarcoma Research Paper Signal Transduction |
| Zdroj: | Oncotarget Repisalud Instituto de Salud Carlos III (ISCIII) Repositorio Institucional de la Consejería de Sanidad de la Comunidad de Madrid Consejería de Sanidad de la Comunidad de Madrid |
| ISSN: | 1949-2553 |
| Popis: | MicroRNAs serve to fine-tune gene expression and play an important regulatory role in tissue specific gene networks. The identification and validation of miRNA target genes in a tissue still poses a significant problem since the presence of a seed sequence in the 3'UTR of an mRNA and its expression modulation upon ectopic expression of the miRNA do not reliably predict regulation under physiological conditions. The chimeric oncoprotein EWS-FLI1 is the driving pathogenic force in Ewing sarcoma. MiR-17-92, one of the most potent oncogenic miRNAs, was recently reported to be among the top EWS-FLI1 activated miRNAs. Using a combination of AGO2 pull-down experiments by PAR-CLIP (Photoactivatable-Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation) and of RNAseq upon miRNA depletion by ectopic sponge expression, we aimed to identify the targetome of miR-17-92 in Ewing sarcoma. Intersecting both datasets we found an enrichment of PAR-CLIP hits for members of the miR-17-92 cluster in the 3'UTRs of genes up-regulated in response to mir-17-92 specific sponge expression. Strikingly, approximately a quarter of these genes annotate to the TGFB/BMP pathway, the majority mapping downstream of SMAD signaling. Testing for SMAD phosphorylation, we identify quiet but activatable TGFB signaling and cell autonomous activity of the BMP pathway resulting in the activation of the stemness regulatory transcriptional repressors ID1 and ID3. Taken together, our findings shed light on the complex miRegulatory landscape of Ewing Sarcoma pointing miR-17-92 as a key node connected to TGFB/BMP pathway. This study was supported in part by the Austrian Science Fund (FWF), [grants 24708-B21 and I1225-B19], and by the 7th framework program of the European Commission, [grant FP7-259348] (‘ASSET’). Sí |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|