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, Hsiao-Fang Sun, Jih-Ing Chuang, Chia-Yih Wang, Bu-Miin Huang

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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 1

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Fibroblast Growth Factor 9
Leydig Cell Tumor
Fibroblast Growth Factor Receptors
Retinoblastoma
Fibroblast Growth Factor 2
Cell Cycle
Cell Proliferation
Cyclin A1
Phosphorylation
Cyclins
G2 Phase
Cell Division
Neoplasms
bcl-1 Genes
Cyclin-Dependent Kinase 4
Cyclin B1
Severe Combined Immunodeficiency

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

@article{32ad464afdf145ae935b0b3e36cb20f1,
title = "FGF9/FGFR2 increase cell proliferation by activating ERK1/2, Rb/E2F1, and cell cycle pathways in mouse Leydig tumor cells",
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.",
author = "Chang, {Ming Min} and Lai, {Meng Shao} and Hong, {Siou Ying} and Pan, {Bo Syong} and Hsin Huang and Shang-Hsun Yang and Chia-Ching Wu and Hsiao-Fang Sun and Jih-Ing Chuang and Chia-Yih Wang and Bu-Miin Huang",
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language = "English",
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FGF9/FGFR2 increase cell proliferation by activating ERK1/2, Rb/E2F1, and cell cycle pathways in mouse Leydig tumor cells. / Chang, Ming Min; Lai, Meng Shao; Hong, Siou Ying; Pan, Bo Syong; Huang, Hsin; Yang, Shang-Hsun; Wu, Chia-Ching; Sun, Hsiao-Fang; Chuang, Jih-Ing; Wang, Chia-Yih; Huang, Bu-Miin.

In: Cancer Science, Vol. 109, No. 11, 01.11.2018, p. 3503-3518.

Research output: Contribution to journalArticle

TY - JOUR

T1 - FGF9/FGFR2 increase cell proliferation by activating ERK1/2, Rb/E2F1, and cell cycle pathways in mouse Leydig tumor cells

AU - Chang, Ming Min

AU - Lai, Meng Shao

AU - Hong, Siou Ying

AU - Pan, Bo Syong

AU - Huang, Hsin

AU - Yang, Shang-Hsun

AU - Wu, Chia-Ching

AU - Sun, Hsiao-Fang

AU - Chuang, Jih-Ing

AU - Wang, Chia-Yih

AU - Huang, Bu-Miin

PY - 2018/11/1

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AB - 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.

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