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FoxM1 Drives a Feed-Forward STAT3-Activation Signaling Loop That Promotes the
Self-Renewal and Tumorigenicity of Glioblastoma Stem-like Cells
#MMPMID25832656
Gong AH
; Wei P
; Zhang S
; Yao J
; Yuan Y
; Zhou AD
; Lang FF
; Heimberger AB
; Rao G
; Huang S
Cancer Res
2015[Jun]; 75
(11
): 2337-48
PMID25832656
show ga
The growth factor PDGF controls the development of glioblastoma (GBM), but its
contribution to the function of GBM stem-like cells (GSC) has been little
studied. Here, we report that the transcription factor FoxM1 promotes PDGFA-STAT3
signaling to drive GSC self-renewal and tumorigenicity. In GBM, we found a
positive correlation between expression of FoxM1 and PDGF-A. In GSC and mouse
neural stem cells, FoxM1 bound to the PDGF-A promoter to upregulate PDGF-A
expression, acting to maintain the stem-like qualities of GSC in part through
this mechanism. Analysis of the human cancer genomic database The Cancer Genome
Atlas revealed that GBM expresses higher levels of STAT3, a PDGF-A effector
signaling molecule, as compared with normal brain. FoxM1 regulated STAT3
transcription through interactions with the ?-catenin/TCF4 complex. FoxM1
deficiency inhibited PDGF-A and STAT3 expression in neural stem cells and GSC,
abolishing their stem-like and tumorigenic properties. Further mechanistic
investigations defined a FoxM1-PDGFA-STAT3 feed-forward pathway that was
sufficient to confer stem-like properties to glioma cells. Collectively, our
findings showed how FoxM1 activates expression of PDGF-A and STAT3 in a pathway
required to maintain the self-renewal and tumorigenicity of glioma stem-like
cells.
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