FGF9/FGFR2 increase cell proliferation by activating ERK1/2, Rb/E2F1, and cell cycle pathways in mouse Leydig tumor cells

Ming Min Chang, Meng Shao Lai, Siou Ying Hong, Bo Syong Pan, Hsin Huang, Shang Hsun Yang, Chia Ching Wu, H. Sunny Sun, Jih Ing Chuang, Chia Yih Wang, Bu Miin Huang

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

Fibroblast growth factor 9 (FGF9) promotes cancer progression; however, its role in cell proliferation related to tumorigenesis remains elusive. We investigated how FGF9 affected MA-10 mouse Leydig tumor cell proliferation and found that FGF9 significantly induced cell proliferation by activating ERK1/2 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 (CDK4) in G1 phase and cyclin A1, CDK2 and CDK1 in S-G2/M phases were increased at 12 hours after FGF9 treatment; and cyclin B1 in G2/M phases were induced at 24 hours after FGF9 stimulation, whereas the phosphorylations of p53, p21 and p27 were not affected by FGF9. Moreover, FGF9-induced effects were inhibited by MEK inhibitor PD98059, indicating FGF9 activated the Rb/E2F pathway to accelerate MA-10 cell proliferation by activating ERK1/2. Immunoprecipitation assay and ChIP-quantitative PCR results showed that FGF9-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 (FGFR2) using lentiviral shRNA inhibited FGF9-induced ERK1/2 phosphorylation and cell proliferation, indicating that FGFR2 is the obligate receptor for FGF9 to bind and activate the signaling pathway in MA-10 cells. Furthermore, in a severe combined immunodeficiency mouse xenograft model, FGF9 significantly promoted MA-10 tumor growth, a consequence of increased cell proliferation and decreased apoptosis. Conclusively, FGF9 interacts with FGFR2 to activate ERK1/2, Rb/E2F1 and cell cycle pathways to induce MA-10 cell proliferation in vitro and tumor growth in vivo.

Original languageEnglish
Pages (from-to)3503-3518
Number of pages16
JournalCancer Science
Volume109
Issue number11
DOIs
Publication statusPublished - 2018 Nov

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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