Abstract
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.
Highlights
Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults
We demonstrated that ADAM8-dependent matrix metalloproteinase 9 (MMP9) expression is mediated via the mitogen-activated protein kinase (MAPK) pathway and resulted in a strong correlation of ADAM8 and MMP9 in breast cancerderived brain metastasis [8]
It is interesting to note that glioblastoma stem-like cells (GSCs) express relatively high levels of miRNA181a5p compared to differentiated GBM cells, which could be instrumental in regulating proliferation and cell survival of this particular cell type
Summary
Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. A disintegrin and metalloproteinases (ADAMs) mediate tumor cell adhesion and migration as well as intracellular signaling [3]. One such proteolytically active family member is the metalloproteinase-disintegrin 8 (ADAM8), strongly associated with tumor aggressiveness, progression, and reduced survival in various cancers including breast cancer, pancreatic ductal adenocarcinoma (PDAC), and GBM [4–7]. ADAM8 dependent activation of the MAPK pathway as well the PI3K/AKT pathway enhanced temozolomidechemoresistance in GBM cell lines [12] Considering these diverse functions of ADAM8 in intracellular signaling, we and others hypothesized that ADAM8 mediates these functions through the regulation of microRNAs and initial evidence came from a study in MDA-MB-231 breast cancer cells showing that ADAM8 regulates expression levels of miR720 [13]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
