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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...

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Autoren: Schäfer, Agnes, Ever, 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.
Format: Artikel
Sprache:Englisch
Veröffentlicht: Philipps-Universität Marburg 2022
Schlagworte:
ADAM8, miR-181a-5p
miRNA
tumor microenvironment
MMP9
glioblastoma
Medizin
extracellular vesicles
MR spectroscopy
Medical sciences Medicine
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Zusammenfassung: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.
Beschreibung:Gefördert durch den Open-Access-Publikationsfonds der UB Marburg.
Umfang:13 Seiten
DOI:10.3389/fonc.2022.826273

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