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FGFR1-ERK1/2-SOX2 axis promotes cell proliferation, epithelial–mesenchymal transition, and metastasis in FGFR1-amplified lung cancer

Oncogene volume 37, pages 5340–5354 (2018)Cite this article

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A Correction to this article was published on 07 September 2020

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Abstract

Epithelial–mesenchymal transition (EMT) is an important process for cancer metastasis, drug resistance, and cancer stem cells. Activation of fibroblast growth factor receptor 1 (FGFR1) was found to promote EMT and metastasis in prostate and breast cancers, but the effects and mechanisms in lung cancer was unclear. In this study, we aimed to explore whether and how activation of FGFR1 promotes EMT and metastasis in FGFR1-amplified lung cancer. We show that activation of FGFR1 by its ligand fibroblast growth factor 2 (FGF2) promoted proliferation, EMT, migration, and invasion in FGFR1-amplified lung cancer cell lines H1581 and DMS114, whereas inhibition of FGFR1 suppressed these processes. FGFR1 activation upregulated expression of Sry-related HMG box 2 (SOX2) by downstream phosphorylated ERK1/2; moreover, the upregulation of SOX2 by autophosphorylation variant ERK2_R67S plasmid transfection was not suppressed by FGFR1 inhibitor AZD4547 or MEK/ERK inhibitor AZD6244 in vitro. And SOX2 expression was also significantly upregulated in ERK2_R67S lentivirus-transfected stable cell lines in vivo. Overexpression of SOX2 promoted cell proliferation, EMT, migration, and invasion. Importantly, activation of FGFR1 could not promote these processes in SOX2-silenced stable cell lines. In orthotopic and subcutaneous lung cancer xenograft models, inhibition of FGFR1 suppressed tumor growth, SOX2 expression, EMT, and metastasis in vivo; however, these processes caused by SOX2-overexpressing stable cell lines were not suppressed by FGFR1 inhibition. Higher expression of FGFR1 and SOX2 were positively correlated, and both were associated with shorter survival in lung cancer patients. In conclusion, our findings reveal that activation of FGFR1 promotes cell proliferation, EMT, and metastasis by the newly defined FGFR1-ERK1/2-SOX2 axis in FGFR1-amplified lung cancer.

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  • 07 September 2020

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Acknowledgements

This work was funded by the National Key R&D Program of China (2016YFC1303300 to S.L.), the National Natural Science Foundation of China (81672272 to S.L. and 81773115 to W.X.), the National Key Grant of China (2016YFC0906400 to W.X.), the Key Project of Shanghai Health & Family Planning Commission (201540365 to S.L.), Shanghai Municipal Science & Technology Commission Research Project (17431906103 to S.L.), and Shanghai Scientific Research Projects (14140902800 to S.L.) We thank Wangxi Hai and Med-X Ruijin Hospital Micro PET/CT Research Center for the microCT scan and analysis. We thank AstraZeneca Pharmaceutical Company for kindly supply of AZD4547 and AstraZeneca Research Funding.

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  1. These authors contributed equally: Kaixuan Wang, Wenxiang Ji.

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  1. Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, West Huaihai Road 241, Shanghai, 200030, China

    Kaixuan Wang, Wenxiang Ji, Yongfeng Yu, Ziming Li, Xiaomin Niu & Shun Lu

  2. School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Huashan Road 1954, Shanghai, 200030, China

    Kaixuan Wang & Weiliang Xia

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Wang, K., Ji, W., Yu, Y. et al. FGFR1-ERK1/2-SOX2 axis promotes cell proliferation, epithelial–mesenchymal transition, and metastasis in FGFR1-amplified lung cancer. Oncogene 37, 5340–5354 (2018). https://doi.org/10.1038/s41388-018-0311-3

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