FGFR3 promotes the growth and malignancy of melanoma by influencing EMT and the phosphorylation of ERK, AKT, and EGFR

Lei Li,Shuai Zhang,Haiyan Chou,Hao Li

doi:10.1186/s12885-019-6161-8

Abstract

BackgroundOverexpression of fibroblast growth factor receptor 3 (FGFR3) has been linked to tumor progression in many types of cancer. The role of FGFR3 in melanoma remains unclear. In this study, we aimed to uncover the role of FGFR3 in the growth and metastasis of melanoma.MethodsFGFR3 knockdown and overexpression strategies were employed to investigate the effects of FGFR3 on colony formation, cell apoptosis, proliferation, migration, and in vitro invasion, along with the growth and metastasis of melanoma in a xenografts mouse model. The protein expression levels of extracellular signal-regulated kinase (ERK), protein kinase B (AKT), epidermal growth factor receptor (EGFR), and epithelial-mesenchymal transition (EMT) markers were determined by Western blot analysis.ResultsThe mRNA expression of FGFR3 was higher in melanoma tissues than normal healthy tissues. FGFR3 expression in cutaneous malignant melanoma (CMM) tissues was positively correlated with the Breslow thickness and lymph node metastasis. In A357 cells, knockdown of the FGFR3 gene decreased the colony formation ability, cell proliferation, invasion, and migration, but increased the caspase 3 activity and the apoptosis rate; overexpression of FGFR3 increased the colony formation ability, cell proliferation, invasion, and migration, but decreased the caspase 3 activity and apoptosis rates. FGFR3 knockdown also upregulated E-cadherin, downregulated N-cadherin and vimentin, and decreased the phosphorylation levels of ERK, AKT, and EGFR. In the MCC xenografts mice, knockdown of FGFR3 decreased tumor growth and metastasis.ConclusionsFGFR3, which is highly expressed in CMM tissues, is correlated with increased Breslow thickness and lymph node metastasis. FGFR3 promotes melanoma growth, metastasis, and EMT behaviors, likely by affecting the phosphorylation levels of ERK, AKT, and EGFR.

Highlights

Overexpression of fibroblast growth factor receptor 3 (FGFR3) has been linked to tumor progression in many types of cancer
The protein expression of FGFR3 in the malignant melanoma tissues was correlated with the Breslow thickness and lymph node metastasis (p < 0.05) (Fig. 1b)
Transient transfection of A357 cells with pcDNA3.0-FGFR3 significantly (p < 0.05) increased the mRNA (Fig. 2c) and protein (Fig. 2d) expression levels of FGFR3 as compared with the cells transfected with the control plasmid

Summary

Introduction

Overexpression of fibroblast growth factor receptor 3 (FGFR3) has been linked to tumor progression in many types of cancer. The role of FGFR3 in melanoma remains unclear. We aimed to uncover the role of FGFR3 in the growth and metastasis of melanoma. Cutaneous malignant melanoma (CMM), which comprises 65% of all skin cancers, is a highly lethal form of skin cancer. Melanoma remains a lethal disease, and new diagnostic and treatment options are needed to improve patient outcomes in the clinic. The fibroblast growth factor receptors (FGFR) comprise a family of transmembrane tyrosine kinase receptors [3] that play vital roles in cell differentiation, growth, and angiogenesis through binding of their respective ligands [4, 5]. Activation of FGFR modulates the cytoplasmic downstream molecules and contributes to its carcinogenesis through signal transducer and activator of transcription protein (STAT), phosphatidylinositide 3-kinases/protein kinase B (PI3K/AKT), and RAS/mitogen activated protein kinase (RAS/MAPK) pathways [4, 6]

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