Open AccessFGF9/FGFR2 increase cell proliferation by activating ERK 1/2, Rb/E2F1, and cell cycle pathways in mouse Leydig tumor cells
Author(s) -
Chang MingMin,
Lai MengShao,
Hong SiouYing,
Pan BoSyong,
Huang Hsin,
Yang ShangHsun,
Wu ChiaChing,
Sun H. Sunny,
Chuang JihIng,
Wang ChiaYih,
Huang BuMiin
Publication year - 2018
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13793
Subject(s) - cyclin d , cyclin d1 , cell growth , cyclin a , cell cycle , fibroblast growth factor , mapk/erk pathway , cyclin dependent kinase , cancer research , microbiology and biotechnology , biology , e2f , chemistry , kinase , cell , biochemistry , receptor
Fibroblast growth factor 9 ( FGF 9) promotes cancer progression; however, its role in cell proliferation related to tumorigenesis remains elusive. We investigated how FGF 9 affected MA ‐10 mouse Leydig tumor cell proliferation and found that FGF 9 significantly induced cell proliferation by activating ERK 1/2 and retinoblastoma (Rb) phosphorylations within 15 minutes. Subsequently, the expressions of E2F1 and the cell cycle regulators: cyclin D1, cyclin E1 and cyclin‐dependent kinase 4 ( CDK 4) in G 1 phase and cyclin A1, CDK 2 and CDK 1 in S‐G 2 /M phases were increased at 12 hours after FGF 9 treatment; and cyclin B1 in G 2 /M phases were induced at 24 hours after FGF 9 stimulation, whereas the phosphorylations of p53, p21 and p27 were not affected by FGF 9. Moreover, FGF 9‐induced effects were inhibited by MEK inhibitor PD 98059, indicating FGF 9 activated the Rb/E2F pathway to accelerate MA ‐10 cell proliferation by activating ERK 1/2. Immunoprecipitation assay and Ch IP ‐quantitative PCR results showed that FGF 9‐induced Rb phosphorylation led to the dissociation of Rb‐E2F1 complexes and thereby enhanced the transactivations of E2F1 target genes, Cyclin D1, Cyclin E1 and Cyclin A1 . Silencing of FGF receptor 2 ( FGFR 2) using lentiviral sh RNA inhibited FGF 9‐induced ERK 1/2 phosphorylation and cell proliferation, indicating that FGFR 2 is the obligate receptor for FGF 9 to bind and activate the signaling pathway in MA ‐10 cells. Furthermore, in a severe combined immunodeficiency mouse xenograft model, FGF 9 significantly promoted MA ‐10 tumor growth, a consequence of increased cell proliferation and decreased apoptosis. Conclusively, FGF 9 interacts with FGFR 2 to activate ERK 1/2, Rb/E2F1 and cell cycle pathways to induce MA ‐10 cell proliferation in vitro and tumor growth in vivo.