Abstract
Mesenchymal transition (MES transition) is a hallmark of glioblastoma multiforme (GBM), however, the mechanism regulating the process remains to be elucidated. Here we report that FoxM1 drives ADAM17/EGFR activation loop to promote MES transition in GBM. Firstly, FoxM1 expression was positively associated with ADAM17 expression, and their expression was correlated with the mesenchymal features and overall patient survival of GBM. Overexpressing FoxM1 or ADAM17 increased the mesenchymal phenotype of glioma cells, which could be reversed by silencing FoxM1 or ADAM17. Importantly, FoxM1 bound to the ADAM17 promoter to transcriptionally upregulate its expression. Using gain- and loss-of-function studies, we showed that FoxM1/ADAM17 axis promoted the MES transition in glioma cells. Moreover, tissue microarray analysis and orthotopic xenograft model further confirmed that FoxM1/ADAM17 axis played key roles in malignancy of GBM. Mechanistically, FoxM1/ADAM17 axis activated the EGFR/AKT/GSK3β signaling pathway and ADAM17/EGFR/GSK3β axis could maintain FoxM1 stability in glioma cells. Taken together, our study demonstrated that FoxM1/ADAM17 feedback loop controlled the MES transition and regulated the progression of GBM, raising the possibility that deregulation of this loop might improve the durability of therapies in GBM.
Highlights
glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults[1,2]
Gene expression heat maps and correlation analysis revealed that the expression of A disintegrin and metalloproteinase 17 (ADAM17) was highly associated with that of FoxM1, both of them were correlated with the expression of mesenchymal markers in GBM (Fig.1a, S1a)
Discussion we clarified that FoxM1 and ADAM17 were coexpressed in GBM, and FoxM1/ADAM17 axis induced MES transition via EGFR/AKT/ GSK3β signaling, which in turn led to the elevated expression of FoxM1
Summary
GBM is the most common malignant primary brain tumor in adults[1,2]. Integrated genomic analyses enable the molecular classification of GBM into neural, proneural, classical and mesenchymal subtypes[3,4]. GBM patients in the mesenchymal subtype exhibit radio- and chemoresistant signature, increased invasiveness, and relatively worse prognosis than proneural subtype[4,5,6]. Recurrences and radio-resistance are associated with the mesenchymal shift in GBM2. It is established that collaboration among transcription factors[6,7,8,9,10], multiple progression. It is critical to elucidate the molecular mechanisms underlying the MES transition in GBM
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