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2 results on '"TGFB/BMP pathway"'

1. The role of miR-17-92 in the miRegulatory landscape of Ewing sarcoma

Author

Schwentner, Raphaela, Herrero-Martin, David, Kauer, Maximilian O, Mutz, Cornelia N, Katschnig, Anna M, Sienski, Grzegorz, Alonso, Javier, Aryee, Dave N T, Kovar, Heinrich, Austrian Science Fund, and Unión Europea. Comisión Europea. 7 Programa Marco

Subjects
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
Abstract

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

Published
2016

2. The role of miR-17-92 in the miRegulatory landscape of Ewing sarcoma.

Author

Schwentner R, Herrero-Martin D, Kauer MO, Mutz CN, Katschnig AM, Sienski G, Alonso J, Aryee DN, and Kovar H

Subjects
Bone Morphogenetic Proteins genetics, Bone Morphogenetic Proteins metabolism, Cell Line, Tumor, Genetic Predisposition to Disease genetics, Humans, Mutation, Oligonucleotide Array Sequence Analysis, Oncogene Proteins, Fusion genetics, Proto-Oncogene Protein c-fli-1 genetics, RNA, Long Noncoding, RNA-Binding Protein EWS genetics, Reverse Transcriptase Polymerase Chain Reaction, Sarcoma, Ewing genetics, Sarcoma, Ewing metabolism, Sarcoma, Ewing pathology, Sequence Analysis, RNA, Signal Transduction genetics, Transforming Growth Factor beta genetics, Transforming Growth Factor beta metabolism, 3' Untranslated Regions genetics, Gene Expression Profiling methods, Gene Expression Regulation, Neoplastic, MicroRNAs genetics
Abstract

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.

Published
2017
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