title: FoxM1 Drives a Feed-Forward STAT3-Activation Signaling Loop That Promotes the Self-Renewal and Tumorigenicity of Glioblastoma Stem-like Cells.
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.
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Cell Biology, School of Medicine, Jiangsu University, Zhenjiang, China.
authors.forename: Ai-Hua
authors.initials: AH
authors.lastname: Gong
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ping
authors.initials: P
authors.lastname: Wei
authors.affiliation: 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.
authors.forename: Sicong
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Neuro-oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jun
authors.initials: J
authors.lastname: Yao
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ai-Dong
authors.initials: AD
authors.lastname: Zhou
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Frederick F
authors.initials: FF
authors.lastname: Lang
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Amy B
authors.initials: AB
authors.lastname: Heimberger
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Rao
authors.affiliation: 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.
authors.forename: Suyun
authors.initials: S
authors.lastname: Huang
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D011401:Promoter Regions, Genetic; D050796:STAT3 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D010982:Platelet-Derived Growth Factor; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C075278:platelet-derived growth factor A
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