Philips Institute of Oral and Craniofacial Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA.
Oral Oncol. 2010 Apr;46(4):e19-24. doi: 10.1016/j.oraloncology.2010.02.006.
Previous work from our laboratory has demonstrated overexpression of chemokines in head and neck cancer and the utility of targeting these proteins for tumor therapy in a preclinical model. However, the mechanisms involved are unexplored. Through gene expression analysis, we found that expression of vascular endothelial growth factor (VEGF-C) was elevated in HN12 cells expressing high levels of CXCL5. In the present study, we have investigated the contribution of VEGF-C to tumor cell growth and motility. RNAi-mediated knockdown of VEGF-C expression in HN12 cells, which express high levels of CXCL5, resulted in a decrease in proliferation. Conversely, forced expression of VEGF-C in HN4 tumor cells with low endogenous CXCL5 levels increased cell growth. Suppression of VEGF-C inhibited migration of HN12 cells. Similarly, HN4 cells showed reduced migration towards conditioned media collected from HN12 cells with VEGF-C knockdown compared to controls, while HN4/VEGF-C conditioned media stimulated cell migration. Moreover, tumor growth in vivo was markedly reduced when VEGF-C expression was blocked by shRNA. Finally, determination of VEGF-C expression in squamous carcinoma cell lines revealed universal overexpression compared to normal keratinocytes. These findings support a role for VEGF-C in head and neck squamous cell carcinogenesis.
先前我们实验室的工作表明趋化因子在头颈部癌症中过度表达，并且这些蛋白质可作为临床前模型中肿瘤治疗的靶点。然而，相关的机制仍未得到探索。通过基因表达分析，我们发现表达高水平 CXCL5 的 HN12 细胞中血管内皮生长因子 (VEGF-C) 的表达升高。在本研究中，我们研究了 VEGF-C 对肿瘤细胞生长和运动性的贡献。在表达高水平 CXCL5 的 HN12 细胞中，通过 RNAi 介导的 VEGF-C 表达下调导致增殖减少。相反，在低内源性 CXCL5 水平的 HN4 肿瘤细胞中强制表达 VEGF-C 会增加细胞生长。抑制 VEGF-C 抑制了 HN12 细胞的迁移。类似地，与对照相比，HN4 细胞向 VEGF-C 敲低的 HN12 细胞收集的条件培养基中的迁移减少，而 HN4/VEGF-C 条件培养基刺激细胞迁移。此外，当通过 shRNA 阻断 VEGF-C 表达时，体内肿瘤生长明显减少。最后，在鳞癌细胞系中测定 VEGF-C 的表达情况显示与正常角质形成细胞相比普遍过表达。这些发现支持 VEGF-C 在头颈部鳞状细胞癌发生中的作用。
