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Tumor suppressor microRNAs are downregulated in myelodysplastic syndrome with spliceosome mutations
Spliceosome mutations are frequently observed in patients with myelodysplastic syndromes (MDS). However, it is largely unknown how these mutations contribute to the disease. MicroRNAs (miRNAs) are small noncoding RNAs, which have been implicated in most human cancers due to their role in post transc...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891095/ https://www.ncbi.nlm.nih.gov/pubmed/26848861 http://dx.doi.org/10.18632/oncotarget.7127 |
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author | Aslan, Derya Garde, Christian Nygaard, Mette Katrine Helbo, Alexandra Søgaard Dimopoulos, Konstantinos Hansen, Jakob Werner Severinsen, Marianne Tang Treppendahl, Marianne Bach Sjø, Lene Dissing Grønbæk, Kirsten Kristensen, Lasse Sommer |
author_facet | Aslan, Derya Garde, Christian Nygaard, Mette Katrine Helbo, Alexandra Søgaard Dimopoulos, Konstantinos Hansen, Jakob Werner Severinsen, Marianne Tang Treppendahl, Marianne Bach Sjø, Lene Dissing Grønbæk, Kirsten Kristensen, Lasse Sommer |
author_sort | Aslan, Derya |
collection | PubMed |
description | Spliceosome mutations are frequently observed in patients with myelodysplastic syndromes (MDS). However, it is largely unknown how these mutations contribute to the disease. MicroRNAs (miRNAs) are small noncoding RNAs, which have been implicated in most human cancers due to their role in post transcriptional gene regulation. The aim of this study was to analyze the impact of spliceosome mutations on the expression of miRNAs in a cohort of 34 MDS patients. In total, the expression of 76 miRNAs, including mirtrons and splice site overlapping miRNAs, was accurately quantified using reverse transcriptase quantitative PCR. The majority of the studied miRNAs have previously been implicated in MDS. Stably expressed miRNA genes for normalization of the data were identified using GeNorm and NormFinder algorithms. High-resolution melting assays covering all mutational hotspots within SF3B1, SRSF2, and U2AF1 (U2AF35) were developed, and all detected mutations were confirmed by Sanger sequencing. Overall, canonical miRNAs were downregulated in spliceosome mutated samples compared to wild-type (P = 0.002), and samples from spliceosome mutated patients clustered together in hierarchical cluster analyses. Among the most downregulated miRNAs were several tumor-suppressor miRNAs, including several let-7 family members, miR-423, and miR-103a. Finally, we observed that the predicted targets of the most downregulated miRNAs were involved in apoptosis, hematopoiesis, and acute myeloid leukemia among other cancer- and metabolic pathways. Our data indicate that spliceosome mutations may play an important role in MDS pathophysiology by affecting the expression of tumor suppressor miRNA genes involved in the development and progression of MDS. |
format | Online Article Text |
id | pubmed-4891095 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-48910952016-06-23 Tumor suppressor microRNAs are downregulated in myelodysplastic syndrome with spliceosome mutations Aslan, Derya Garde, Christian Nygaard, Mette Katrine Helbo, Alexandra Søgaard Dimopoulos, Konstantinos Hansen, Jakob Werner Severinsen, Marianne Tang Treppendahl, Marianne Bach Sjø, Lene Dissing Grønbæk, Kirsten Kristensen, Lasse Sommer Oncotarget Research Paper Spliceosome mutations are frequently observed in patients with myelodysplastic syndromes (MDS). However, it is largely unknown how these mutations contribute to the disease. MicroRNAs (miRNAs) are small noncoding RNAs, which have been implicated in most human cancers due to their role in post transcriptional gene regulation. The aim of this study was to analyze the impact of spliceosome mutations on the expression of miRNAs in a cohort of 34 MDS patients. In total, the expression of 76 miRNAs, including mirtrons and splice site overlapping miRNAs, was accurately quantified using reverse transcriptase quantitative PCR. The majority of the studied miRNAs have previously been implicated in MDS. Stably expressed miRNA genes for normalization of the data were identified using GeNorm and NormFinder algorithms. High-resolution melting assays covering all mutational hotspots within SF3B1, SRSF2, and U2AF1 (U2AF35) were developed, and all detected mutations were confirmed by Sanger sequencing. Overall, canonical miRNAs were downregulated in spliceosome mutated samples compared to wild-type (P = 0.002), and samples from spliceosome mutated patients clustered together in hierarchical cluster analyses. Among the most downregulated miRNAs were several tumor-suppressor miRNAs, including several let-7 family members, miR-423, and miR-103a. Finally, we observed that the predicted targets of the most downregulated miRNAs were involved in apoptosis, hematopoiesis, and acute myeloid leukemia among other cancer- and metabolic pathways. Our data indicate that spliceosome mutations may play an important role in MDS pathophysiology by affecting the expression of tumor suppressor miRNA genes involved in the development and progression of MDS. Impact Journals LLC 2016-02-02 /pmc/articles/PMC4891095/ /pubmed/26848861 http://dx.doi.org/10.18632/oncotarget.7127 Text en Copyright: © 2016 Aslan et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Aslan, Derya Garde, Christian Nygaard, Mette Katrine Helbo, Alexandra Søgaard Dimopoulos, Konstantinos Hansen, Jakob Werner Severinsen, Marianne Tang Treppendahl, Marianne Bach Sjø, Lene Dissing Grønbæk, Kirsten Kristensen, Lasse Sommer Tumor suppressor microRNAs are downregulated in myelodysplastic syndrome with spliceosome mutations |
title | Tumor suppressor microRNAs are downregulated in myelodysplastic syndrome with spliceosome mutations |
title_full | Tumor suppressor microRNAs are downregulated in myelodysplastic syndrome with spliceosome mutations |
title_fullStr | Tumor suppressor microRNAs are downregulated in myelodysplastic syndrome with spliceosome mutations |
title_full_unstemmed | Tumor suppressor microRNAs are downregulated in myelodysplastic syndrome with spliceosome mutations |
title_short | Tumor suppressor microRNAs are downregulated in myelodysplastic syndrome with spliceosome mutations |
title_sort | tumor suppressor micrornas are downregulated in myelodysplastic syndrome with spliceosome mutations |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891095/ https://www.ncbi.nlm.nih.gov/pubmed/26848861 http://dx.doi.org/10.18632/oncotarget.7127 |
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