Neuropilin-1 promotes epithelial-to-mesenchymal transition by stimulating nuclear factor-kappa B and is associated with poor prognosis in human oral squamous cell carcinoma.

Weiming Chu,Lu Ma,Xueming Yang,Yunong Wu,Mengying He,Zilu Wang,Xiaomeng Song,Jiang Zhu,Jung Weon Lee

doi:10.1371/journal.pone.0101931

Weiming Chu, Lu Ma + Show 7 more

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https://doi.org/10.1371/journal.pone.0101931

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Abstract

BackgroundThe epithelial-to-mesenchymal transition (EMT) is a key process in carcinogenesis, invasion, and metastasis of oral squamous cell carcinoma (OSCC). In our previous studies, we found that neuropilin-1 (NRP1) is overexpressed in tongue squamous cell carcinoma and that this overexpression is associated with cell migration and invasion. Nuclear factor-kappa B (NF-κB) plays an essential role both in the induction and the maintenance of EMT and tumor metastasis. Therefore, we hypothesized that NRP1 induces EMT, and that NRP1-induced migration and invasion may be an important mechanism for promoting invasion and metastasis of OSCC through NF-κB activation.Methods/ResultsThe variations in gene and protein expression and the changes in the biological behavior of OSCC cell lines transfected with a vector encoding NRP1, or the corresponding vector control, were evaluated. NRP1 overexpression promoted EMT and was associated with enhanced invasive and metastatic properties. Furthermore, the induction of EMT promoted the acquisition of some cancer stem cell (CSC)-like characteristics in OSCC cells. We addressed whether selective inhibition of NF-κB suppresses the NRP1-mediated EMT by treating cells with pyrrolidinedithiocarbamate ammonium (PDTC), an inhibitor of NF-κB. Immunohistochemical analysis of NRP1 in OSCC tissue samples further supported a key mediator role for NRP1 in tumor progression, lymph node metastasis, and indicated that NRP1 is a predictor for poor prognosis in OSCC patients.ConclusionOur results indicate that NRP1 may regulate the EMT process in OSCC cell lines through NF-κB activation, and that higher NRP1 expression levels are associated with lymph node metastasis and poor prognosis in OSCC patients. Further investigation of the role of NRP1 in tumorigenesis may help identify novel targets for the prevention and therapy of oral cancers.

Highlights

Oral squamous cell carcinoma (OSCC) is a major cause of morbidity and mortality worldwide, accounting for at least 90% of all oral malignancies
Our results indicate that NRP1 may regulate the epithelial-to-mesenchymal transition (EMT) process in oral squamous cell carcinoma (OSCC) cell lines through Nuclear factor-kappa B (NF-kB) activation, and that higher NRP1 expression levels are associated with lymph node metastasis and poor prognosis in OSCC patients
We investigated the role of NRP1 as an enhancer of the EMT process, through NF-kB activation, in OSCC cells

Summary

Introduction

Oral squamous cell carcinoma (OSCC) is a major cause of morbidity and mortality worldwide, accounting for at least 90% of all oral malignancies. Accumulating lines of evidence have shown that the epithelial-to-mesenchymal transition (EMT) contributes to tumor metastasis and invasion [2,3,4,5]. After activation of the EMT -process, tumor cells lose their epithelial features, including cell adhesion and polarity, reorganize their cytoskeleton, and acquire a mesenchymal morphology and the ability to migrate [5]. The epithelial-to-mesenchymal transition (EMT) is a key process in carcinogenesis, invasion, and metastasis of oral squamous cell carcinoma (OSCC). We found that neuropilin-1 (NRP1) is overexpressed in tongue squamous cell carcinoma and that this overexpression is associated with cell migration and invasion. We hypothesized that NRP1 induces EMT, and that NRP1-induced migration and invasion may be an important mechanism for promoting invasion and metastasis of OSCC through NF-kB activation

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Discussion

Conclusion