title: Regulation of brachyury by fibroblast growth factor receptor 1 in lung cancer.
abstract: Recent evidence suggests that T-box transcription factor brachyury plays an important role in lung cancer development and progression. However, the mechanisms underlying brachyury-driven cellular processes remain unclear. Here we found that fibroblast growth factor receptor 1/mitogen-activated protein kinase (FGFR1/MAPK) signaling regulated brachyury in lung cancer. Analysis of FGFR1-4 and brachyury expression in human lung tumor tissue and cell lines found that only expression of FGFR1 was positively correlated with brachyury expression. Specific knockdown of FGFR1 by siRNA suppressed brachyury expression and epithelial-mesenchymal transition (EMT) (upregulation of E-cadherin and β-catenin and downregulation of Snail and fibronectin), whereas forced overexpression of FGFR1 induced brachyury expression and promoted EMT in lung cancer cells. Activation of fibroblast growth factor (FGF)/FGFR1 signaling promoted phosphorylated MAPK extracellular signal-regulated kinase (ERK) 1/2 translocation from cytoplasm to nucleus, upregulated brachyury expression, and increased cell growth and invasion. In addition, human lung cancer cells with higher brachyury expression were more sensitive to inhibitors targeting FGFR1/MAPK pathway. These findings suggest that FGFR1/MAPK may be important for brachyury activation in lung cancer, and this pathway may be an appealing therapeutic target for a subset of brachyury-driven lung cancer.
authors.affiliation: Department of Neurosurgery, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
authors.forename: Yunping
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Otolaryngology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Feng
authors.affiliation: Department of Radiology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
authors.forename: Akiva
authors.initials: A
authors.lastname: Mintz
authors.affiliation: Department of Hematology and Oncology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
authors.forename: W Jeffrey
authors.initials: WJ
authors.lastname: Petty
authors.affiliation: Department of Neurosurgery, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
authors.forename: Wesley
authors.initials: W
authors.lastname: Hsu
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition; D005326:Fetal Proteins / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D009361:Neoplasm Invasiveness; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000032:analysis / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D020825:T-Box Domain Proteins / Q000502:physiology*; D000098908:Brachyury Protein
chemical_list: D005326:Fetal Proteins; D051496:Receptor, Fibroblast Growth Factor, Type 1; D020825:T-Box Domain Proteins; D000098908:Brachyury Protein; C496348:FGFR1 protein, human
keywords: brachyury; extracellular signal-regulated kinase; fibroblast growth factor receptor 1; lung cancer; mitogen-activated protein kinase