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Negative control of the HGF/c-MET pathway by TGF-?: a new look at the regulation
of stemness in glioblastoma
#MMPMID29238047
Papa E
; Weller M
; Weiss T
; Ventura E
; Burghardt I
; Szabó E
Cell Death Dis
2017[Dec]; 8
(12
): 3210
PMID29238047
show ga
Multiple target inhibition has gained considerable interest in combating drug
resistance in glioblastoma, however, understanding the molecular mechanisms of
crosstalk between signaling pathways and predicting responses of cancer cells to
targeted interventions has remained challenging. Despite the significant role
attributed to transforming growth factor (TGF)-? family and hepatocyte growth
factor (HGF)/c-MET signaling in glioblastoma pathogenesis, their functional
interactions have not been well characterized. Using genetic and pharmacological
approaches to stimulate or antagonize the TGF-? pathway in human
glioma-initiating cells (GIC), we observed that TGF-? exerts an inhibitory effect
on c-MET phosphorylation. Inhibition of either mitogen-activated protein kinase
(MAPK)/ extracellular signal-regulated kinase (ERK) or phosphatidylinositol
3-kinase (PI3K)/protein kinase B (PKB/AKT) signaling pathway attenuated this
effect. A comparison of c-MET-driven and c-MET independent GIC models revealed
that TGF-? inhibits stemness in GIC at least in part via its negative regulation
of c-MET activity, suggesting that stem cell (SC) maintenance may be controlled
by the balance between these two oncogenic pathways. Importantly,
immunohistochemical analyses of human glioblastoma and ex vivo single-cell gene
expression profiling of TGF-? and HGF confirm the negative interaction between
both pathways. These novel insights into the crosstalk of two major pathogenic
pathways in glioblastoma may explain some of the disappointing results when
targeting either pathway alone in human glioblastoma patients and inform on
potential future designs on targeted pharmacological or genetic intervention.
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