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Y. Zhang, J. Jester, P. Reinach, W. Kao, C.-Y. Liu; Fgf7 Stimulates Proliferation and Expression of Angiogenic Factors of Human Corneal Epithelial Cells. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2590.
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© ARVO (1962-2015); The Authors (2016-present)
FGF7 (Fibroblast Growth Factor 7, also known as KGF: Keratinocyte growth Factor) secreted by mesenchymal cells is a potent epithelial cell growth factor. Our previous results showed that doxycycline induced over production of FGF7 by corneal epithelial cells of Krt12rtTA/rtTA/ tetO-FGF7 double transgenic mice caused a corneal papillomatous squamous cell carcinoma with angiogenesis. In the present study, we examined the signaling pathway(s) triggered by FGF7 in human telomerase immortalized corneal epithelial cell line (HTCE) in attempt to determine the signaling pathways underlying the pathogenesis caused by excess FGF7 in vivo.
HTCE cells were plated in p100 culture plates. Total protein lysates of non-treated and FGF7-treated cells were subjected to western blot analysis with rabbit Anti-phospo-ERK1/2 , anti-GSK3β, anti-phospho-GSK3β (ser9) and anti-β-catenin antibodies, respectively. β-Catenin subcellular localization was examined by immunocytochemistry. Real-time PCR was performed to determine the mRNA expression levels of VEGFR1, VEGFA, cyclin D1 and c-myc.
FGF7 induced phospho-ERK1/2 up-regulation, increased phosphorylated GSK-3β (ser-9) level and promoted nuclear translocation of β-catenin in HTCE cells. Both cyclin D1 and c-myc expression level were up-regulated by 2.5 and 1.8 fold, respectively. The effects of FGF7 on cell growth and the expression of cyclin D1 and c-myc was blocked by PI3K inhibitor (LY294002), but not by MEK inhibitor (U0126) in HTCE cells. Administration of FGF7 increased the expression of VEGFA and VEGFR1 by 2.5 fold and 5.6 fold, respectively.
These data suggest that PI3K rather than MAPK pathway mediates FGF7 signaling via inactivation of GSK-3β that leads to stabilization and nuclear translocation of β-catenin and consequent enhanced epithelial cell proliferation and angiogenic factor expression by corneal epithelial cells.
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