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Cancer Res. 2015 Jun 1;75(11):2337-48. doi: 10.1158/0008-5472.CAN-14-2800. Epub 2015 Apr 1.

FoxM1 Drives a Feed-Forward STAT3-Activation Signaling Loop That Promotes the Self-Renewal and Tumorigenicity of Glioblastoma Stem-like Cells.

Author information

1
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Cell Biology, School of Medicine, Jiangsu University, Zhenjiang, China.
2
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
3
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas. Program in Cancer Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas.
4
Department of Neuro-oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
5
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
6
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas. Program in Cancer Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas. suhuang@mdanderson.org.

Abstract

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 β-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.

PMID:
25832656
PMCID:
PMC4452436
DOI:
10.1158/0008-5472.CAN-14-2800
[Indexed for MEDLINE]
Free PMC Article

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