Cargando…
Complex Epigenetic Regulation of Chemotherapy Resistance and Biology in Esophageal Squamous Cell Carcinoma via MicroRNAs
Background: Resistance towards chemotherapy is a major obstacle in the treatment of esophageal squamous cell carcinoma (ESCC). We investigated the role of specific microRNAs in chemotherapy resistance and tumor biology. Methods: We selected three microRNAs from characteristic microRNA signatures of...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855721/ https://www.ncbi.nlm.nih.gov/pubmed/29414899 http://dx.doi.org/10.3390/ijms19020499 |
_version_ | 1783307163271168000 |
---|---|
author | Lindner, Kirsten Eichelmann, Ann-Kathrin Matuszcak, Christiane Hussey, Damian James Haier, Jörg Hummel, Richard |
author_facet | Lindner, Kirsten Eichelmann, Ann-Kathrin Matuszcak, Christiane Hussey, Damian James Haier, Jörg Hummel, Richard |
author_sort | Lindner, Kirsten |
collection | PubMed |
description | Background: Resistance towards chemotherapy is a major obstacle in the treatment of esophageal squamous cell carcinoma (ESCC). We investigated the role of specific microRNAs in chemotherapy resistance and tumor biology. Methods: We selected three microRNAs from characteristic microRNA signatures of resistant ESCC (hsa-miR-125a-5p, hsa-miR-130a-3p, hsa-miR-1226-3p), and hsa-miR-148a-3p. Effects on chemotherapy, adhesion, migration, apoptosis and cell cycle were assessed in six ESCC cell lines. Target analyses were performed using Western blotting and luciferase techniques. Results: MiR-130a-3p sensitized cells towards cisplatin in 100% of cell lines, miR-148a-3p in 83%, miR-125a-5p in 67%, miR-1226-3p in 50% (p ≤ 0.04). MiR-130a-3p sensitized 83% of cell lines towards 5-FU, miR-148a-3p/miR-125a-5p/miR-1226-3p only 33% (p ≤ 0.015). Several resistance-relevant pathways seem to be targeted on various levels. Bcl-2 was confirmed as a direct target of miR-130a-3p and miR-148a-3p, and p53 as a target of miR-125a-5p. All microRNAs decreased migration and adhesion, except miR-130a-3p, and increased apoptosis. Simultaneous manipulation of two microRNAs exhibited additive sensitizing effects towards cisplatin in 50% (miR-125a-5p/miR-148a-3p), and 75% (miR-148a-3p/miR-130a-3p) of cell lines (p ≤ 0.006). Conclusion: Our data present strong evidence that specific microRNA signatures are responsible for drug resistance and aggressiveness of ESCC. Final functional readout of these complex processes appears to be more important than single microRNA-target interactions. |
format | Online Article Text |
id | pubmed-5855721 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-58557212018-03-20 Complex Epigenetic Regulation of Chemotherapy Resistance and Biology in Esophageal Squamous Cell Carcinoma via MicroRNAs Lindner, Kirsten Eichelmann, Ann-Kathrin Matuszcak, Christiane Hussey, Damian James Haier, Jörg Hummel, Richard Int J Mol Sci Article Background: Resistance towards chemotherapy is a major obstacle in the treatment of esophageal squamous cell carcinoma (ESCC). We investigated the role of specific microRNAs in chemotherapy resistance and tumor biology. Methods: We selected three microRNAs from characteristic microRNA signatures of resistant ESCC (hsa-miR-125a-5p, hsa-miR-130a-3p, hsa-miR-1226-3p), and hsa-miR-148a-3p. Effects on chemotherapy, adhesion, migration, apoptosis and cell cycle were assessed in six ESCC cell lines. Target analyses were performed using Western blotting and luciferase techniques. Results: MiR-130a-3p sensitized cells towards cisplatin in 100% of cell lines, miR-148a-3p in 83%, miR-125a-5p in 67%, miR-1226-3p in 50% (p ≤ 0.04). MiR-130a-3p sensitized 83% of cell lines towards 5-FU, miR-148a-3p/miR-125a-5p/miR-1226-3p only 33% (p ≤ 0.015). Several resistance-relevant pathways seem to be targeted on various levels. Bcl-2 was confirmed as a direct target of miR-130a-3p and miR-148a-3p, and p53 as a target of miR-125a-5p. All microRNAs decreased migration and adhesion, except miR-130a-3p, and increased apoptosis. Simultaneous manipulation of two microRNAs exhibited additive sensitizing effects towards cisplatin in 50% (miR-125a-5p/miR-148a-3p), and 75% (miR-148a-3p/miR-130a-3p) of cell lines (p ≤ 0.006). Conclusion: Our data present strong evidence that specific microRNA signatures are responsible for drug resistance and aggressiveness of ESCC. Final functional readout of these complex processes appears to be more important than single microRNA-target interactions. MDPI 2018-02-07 /pmc/articles/PMC5855721/ /pubmed/29414899 http://dx.doi.org/10.3390/ijms19020499 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Lindner, Kirsten Eichelmann, Ann-Kathrin Matuszcak, Christiane Hussey, Damian James Haier, Jörg Hummel, Richard Complex Epigenetic Regulation of Chemotherapy Resistance and Biology in Esophageal Squamous Cell Carcinoma via MicroRNAs |
title | Complex Epigenetic Regulation of Chemotherapy Resistance and Biology in Esophageal Squamous Cell Carcinoma via MicroRNAs |
title_full | Complex Epigenetic Regulation of Chemotherapy Resistance and Biology in Esophageal Squamous Cell Carcinoma via MicroRNAs |
title_fullStr | Complex Epigenetic Regulation of Chemotherapy Resistance and Biology in Esophageal Squamous Cell Carcinoma via MicroRNAs |
title_full_unstemmed | Complex Epigenetic Regulation of Chemotherapy Resistance and Biology in Esophageal Squamous Cell Carcinoma via MicroRNAs |
title_short | Complex Epigenetic Regulation of Chemotherapy Resistance and Biology in Esophageal Squamous Cell Carcinoma via MicroRNAs |
title_sort | complex epigenetic regulation of chemotherapy resistance and biology in esophageal squamous cell carcinoma via micrornas |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855721/ https://www.ncbi.nlm.nih.gov/pubmed/29414899 http://dx.doi.org/10.3390/ijms19020499 |
work_keys_str_mv | AT lindnerkirsten complexepigeneticregulationofchemotherapyresistanceandbiologyinesophagealsquamouscellcarcinomaviamicrornas AT eichelmannannkathrin complexepigeneticregulationofchemotherapyresistanceandbiologyinesophagealsquamouscellcarcinomaviamicrornas AT matuszcakchristiane complexepigeneticregulationofchemotherapyresistanceandbiologyinesophagealsquamouscellcarcinomaviamicrornas AT husseydamianjames complexepigeneticregulationofchemotherapyresistanceandbiologyinesophagealsquamouscellcarcinomaviamicrornas AT haierjorg complexepigeneticregulationofchemotherapyresistanceandbiologyinesophagealsquamouscellcarcinomaviamicrornas AT hummelrichard complexepigeneticregulationofchemotherapyresistanceandbiologyinesophagealsquamouscellcarcinomaviamicrornas |