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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|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.
|Gefördert durch den Open-Access-Publikationsfonds der UB Marburg.