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

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.

PAX2 regulates NRP-1 expression in renal tubular epithelial cellsto promote epithelial-to-mesenchymal transition and renal fibrosis

“…Studies have suggested that overexpressed NRP-1 can induce EMT in oral squamous cell carcinoma cells and human gastric cancer cells [10,24] . Three signaling pathways are involved in EMT induced by NRP-1: TGF-induce EMT in oral scMet.…”

“…NRP-1, initially discovered in the developing nerve fiber axons, is a receptor of semaphorin 3A and vascular endothelial growth factor (VEGF)-165 and is mainly expressed in glomerular epithelial cells and collecting ducts [9] . Studies have suggested that NRP-1 can induce EMT in tumor cells [10] , and its expression is increased in hepatic fibrosis [11,12] . Considering the importance of PAX2-induced EMT in renal tubular epithelial cells and its relationship with NRP-1, we selected NRP-1 as a candidate target gene and we hypothesized that PAX2 regulates NRP-1 expression in renal tubular epithelial cells, and that NRP-1 is involved in RIF.…”

Anticancer effects of valproic acid on oral squamous cell carcinoma via SUMOylation in vivo and in vitro

“…Oral squamous cell carcinoma is the most frequently occurring malignant oral tumor in the oral cancer group (2); however, to the best of our knowledge, the effectiveness of VPA on OSCC has not been widely investigated. In the present study, the effects of VPA on OSCC were examined in vivo and in vitro .…”

“…OSCC is a complex disease associated with numerous changes in genetic and epigenetic interactions; however, the mechanisms remain poorly understood (2). Alterations in the histone acetylation/deacetylation balance, have been suggested to underpin the altered gene expression patterns detected in various pathological conditions, including cancer (3) and cardiac hypertrophy (4,5).…”

Notch and Wnt signaling pathway in cancer: Crucial role and potential therapeutic targets (Review)

“…A recent report showed that high Notch1 expression is associated with low survival rate in esophageal squamous cell cancer (10). Furthermore, Chu et al (11) reported that nuclear factorkappa B also influences the prognosis of oral squamous cell carcinoma. In addition, Wnt5a positivity was reported as a sign of short survival period in NSCLC (12).…”