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The Metalloprotease-Disintegrin ADAM8 Alters the Tumor Suppressor miR-181a-5p Expression Profile in Glioblastoma Thereby Contributing to Its Aggressiveness
Glioblastoma (GBM) as the most common and aggressive brain tumor is characterized by genetic heterogeneity, invasiveness, radio-/chemoresistance, and occurrence of GBM stem-like cells. The metalloprotease-disintegrin ADAM8 is highly expressed in GBM tumor and immune cells and correlates with poor su...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8964949/ https://www.ncbi.nlm.nih.gov/pubmed/35371977 http://dx.doi.org/10.3389/fonc.2022.826273 |
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author | Schäfer, Agnes Evers, Lara Meier, Lara Schlomann, Uwe Bopp, Miriam H. A. Dreizner, Gian-Luca Lassmann, Olivia Ben Bacha, Aaron Benescu, Andreea-Cristina Pojskic, Mirza Preußer, Christian von Strandmann, Elke Pogge Carl, Barbara Nimsky, Christopher Bartsch, Jörg W. |
author_facet | Schäfer, Agnes Evers, Lara Meier, Lara Schlomann, Uwe Bopp, Miriam H. A. Dreizner, Gian-Luca Lassmann, Olivia Ben Bacha, Aaron Benescu, Andreea-Cristina Pojskic, Mirza Preußer, Christian von Strandmann, Elke Pogge Carl, Barbara Nimsky, Christopher Bartsch, Jörg W. |
author_sort | Schäfer, Agnes |
collection | PubMed |
description | Glioblastoma (GBM) as the most common and aggressive brain tumor is characterized by genetic heterogeneity, invasiveness, radio-/chemoresistance, and occurrence of GBM stem-like cells. The metalloprotease-disintegrin ADAM8 is highly expressed in GBM tumor and immune cells and correlates with poor survival. In GBM, ADAM8 affects intracellular kinase signaling and increases expression levels of osteopontin/SPP1 and matrix metalloproteinase 9 (MMP9) by an unknown mechanism. Here we explored whether microRNA (miRNA) expression levels could be regulators of MMP9 expression in GBM cells expressing ADAM8. Initially, we identified several miRNAs as dysregulated in ADAM8-deficient U87 GBM cells. Among these, the tumor suppressor miR-181a-5p was significantly upregulated in ADAM8 knockout clones. By inhibiting kinase signaling, we found that ADAM8 downregulates expression of miR-181a-5p via activation of signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase (MAPK) signaling suggesting an ADAM8-dependent silencing of miR-181a-5p. In turn, mimic miR-181a-5p transfection caused decreased cell proliferation and lower MMP9 expression in GBM cells. Furthermore, miR-181a-5p was detected in GBM cell-derived extracellular vesicles (EVs) as well as patient serum-derived EVs. We identified miR-181a-5p downregulating MMP9 expression via targeting the MAPK pathway. Analysis of patient tissue samples (n=22) revealed that in GBM, miR-181a-5p is strongly downregulated compared to ADAM8 and MMP9 mRNA expression, even in localized tumor areas. Taken together, we provide evidence for a functional axis involving ADAM8/miR-181a-5p/MAPK/MMP9 in GBM tumor cells. |
format | Online Article Text |
id | pubmed-8964949 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-89649492022-03-31 The Metalloprotease-Disintegrin ADAM8 Alters the Tumor Suppressor miR-181a-5p Expression Profile in Glioblastoma Thereby Contributing to Its Aggressiveness Schäfer, Agnes Evers, Lara Meier, Lara Schlomann, Uwe Bopp, Miriam H. A. Dreizner, Gian-Luca Lassmann, Olivia Ben Bacha, Aaron Benescu, Andreea-Cristina Pojskic, Mirza Preußer, Christian von Strandmann, Elke Pogge Carl, Barbara Nimsky, Christopher Bartsch, Jörg W. Front Oncol Oncology Glioblastoma (GBM) as the most common and aggressive brain tumor is characterized by genetic heterogeneity, invasiveness, radio-/chemoresistance, and occurrence of GBM stem-like cells. The metalloprotease-disintegrin ADAM8 is highly expressed in GBM tumor and immune cells and correlates with poor survival. In GBM, ADAM8 affects intracellular kinase signaling and increases expression levels of osteopontin/SPP1 and matrix metalloproteinase 9 (MMP9) by an unknown mechanism. Here we explored whether microRNA (miRNA) expression levels could be regulators of MMP9 expression in GBM cells expressing ADAM8. Initially, we identified several miRNAs as dysregulated in ADAM8-deficient U87 GBM cells. Among these, the tumor suppressor miR-181a-5p was significantly upregulated in ADAM8 knockout clones. By inhibiting kinase signaling, we found that ADAM8 downregulates expression of miR-181a-5p via activation of signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase (MAPK) signaling suggesting an ADAM8-dependent silencing of miR-181a-5p. In turn, mimic miR-181a-5p transfection caused decreased cell proliferation and lower MMP9 expression in GBM cells. Furthermore, miR-181a-5p was detected in GBM cell-derived extracellular vesicles (EVs) as well as patient serum-derived EVs. We identified miR-181a-5p downregulating MMP9 expression via targeting the MAPK pathway. Analysis of patient tissue samples (n=22) revealed that in GBM, miR-181a-5p is strongly downregulated compared to ADAM8 and MMP9 mRNA expression, even in localized tumor areas. Taken together, we provide evidence for a functional axis involving ADAM8/miR-181a-5p/MAPK/MMP9 in GBM tumor cells. Frontiers Media S.A. 2022-03-15 /pmc/articles/PMC8964949/ /pubmed/35371977 http://dx.doi.org/10.3389/fonc.2022.826273 Text en Copyright © 2022 Schäfer, Evers, Meier, Schlomann, Bopp, Dreizner, Lassmann, Ben Bacha, Benescu, Pojskic, Preußer, von Strandmann, Carl, Nimsky and Bartsch https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Schäfer, Agnes Evers, Lara Meier, Lara Schlomann, Uwe Bopp, Miriam H. A. Dreizner, Gian-Luca Lassmann, Olivia Ben Bacha, Aaron Benescu, Andreea-Cristina Pojskic, Mirza Preußer, Christian von Strandmann, Elke Pogge Carl, Barbara Nimsky, Christopher Bartsch, Jörg W. The Metalloprotease-Disintegrin ADAM8 Alters the Tumor Suppressor miR-181a-5p Expression Profile in Glioblastoma Thereby Contributing to Its Aggressiveness |
title | The Metalloprotease-Disintegrin ADAM8 Alters the Tumor Suppressor miR-181a-5p Expression Profile in Glioblastoma Thereby Contributing to Its Aggressiveness |
title_full | The Metalloprotease-Disintegrin ADAM8 Alters the Tumor Suppressor miR-181a-5p Expression Profile in Glioblastoma Thereby Contributing to Its Aggressiveness |
title_fullStr | The Metalloprotease-Disintegrin ADAM8 Alters the Tumor Suppressor miR-181a-5p Expression Profile in Glioblastoma Thereby Contributing to Its Aggressiveness |
title_full_unstemmed | The Metalloprotease-Disintegrin ADAM8 Alters the Tumor Suppressor miR-181a-5p Expression Profile in Glioblastoma Thereby Contributing to Its Aggressiveness |
title_short | The Metalloprotease-Disintegrin ADAM8 Alters the Tumor Suppressor miR-181a-5p Expression Profile in Glioblastoma Thereby Contributing to Its Aggressiveness |
title_sort | metalloprotease-disintegrin adam8 alters the tumor suppressor mir-181a-5p expression profile in glioblastoma thereby contributing to its aggressiveness |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8964949/ https://www.ncbi.nlm.nih.gov/pubmed/35371977 http://dx.doi.org/10.3389/fonc.2022.826273 |
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