Chu Weiming, Song Xiaomeng, Yang Xueming, Ma Lu, Zhu Jiang, He Mengying, Wang Zilu, Wu Yunong
Institute of Stomatology, Nanjing Medical University, Nanjing, PR China; Department of Oral and Maxillofacial Surgery, Stomatological Hospital of Jiangsu Province, Nanjing, PR China.
Department of Oral and Maxillofacial Surgery, Stomatological Hospital of Jiangsu Province, Nanjing, PR China.
PLoS One. 2014 Jul 7;9(7):e101931. doi: 10.1371/journal.pone.0101931. eCollection 2014.
The 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/RESULTS: The 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.
Our 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.
上皮-间质转化（EMT）是口腔鳞状细胞癌（OSCC）发生、侵袭和转移的关键过程。在我们之前的研究中，我们发现神经纤毛蛋白-1（NRP1）在舌鳞状细胞癌中过表达，且这种过表达与细胞迁移和侵袭相关。核因子-κB（NF-κB）在EMT的诱导和维持以及肿瘤转移中起着至关重要的作用。因此，我们推测NRP1诱导EMT，并且NRP1诱导的迁移和侵袭可能是通过激活NF-κB促进OSCC侵袭和转移的重要机制。
方法/结果：评估了用编码NRP1的载体或相应载体对照转染的OSCC细胞系的基因和蛋白表达变化以及生物学行为变化。NRP1过表达促进了EMT，并与增强的侵袭和转移特性相关。此外，EMT的诱导促进了OSCC细胞中一些癌症干细胞（CSC）样特征的获得。我们通过用NF-κB抑制剂吡咯烷二硫代氨基甲酸铵（PDTC）处理细胞，探讨了选择性抑制NF-κB是否能抑制NRP1介导的EMT。对OSCC组织样本中NRP1的免疫组化分析进一步支持了NRP1在肿瘤进展、淋巴结转移中的关键介导作用，并表明NRP1是OSCC患者预后不良的预测指标。
我们的结果表明，NRP1可能通过激活NF-κB调节OSCC细胞系中的EMT过程，并且较高的NRP1表达水平与OSCC患者的淋巴结转移和预后不良相关。进一步研究NRP1在肿瘤发生中的作用可能有助于确定口腔癌预防和治疗的新靶点。
