Department of Anatomy and Histology, Harbin Medical University, Harbin 150081, China; Department of Anatomy and Histology, Mudanjiang Medical University, Mudanjiang 157011, China.
Eur J Cancer. 2011 Oct;47(15):2353-63. doi: 10.1016/j.ejca.2011.05.006. Epub 2011 Jun 15.
Vascular endothelial growth factor C (VEGF-C) expression is associated with the malignant tumour phenotype making it an attractive therapeutic target. We investigated the biological roles of VEGF-C in tumour growth, migration, invasion and explored the possibility of VEGF-C as a potential therapeutic target for the treatment of non-small cell lung cancer (NSCLC). A lentivirus-mediated RNA interference (RNAi) technology was used to specifically knockdown the expression of VEGF-C in A549 cells. Quantitative reverse transcriptase-polymerase chain reaction, flow cytometry, Western blot, immunohistochemistry, cellular growth, migration, invasion and ELISA assays were used to characterise VEGF-C expression in vitro. A lung cancer xenograft model in nude mice was established to investigate whether knockdown of VEGF-C reduced tumour growth in vivo. Silencing of VEGF-C suppressed tumour cell growth, migration and invasion in vitro; suppressed tumour growth, angiogenesis and lymphangiogenesis by tail vein injection of lentivirus encoded shRNA against VEGF-C in vivo. More importantly, silencing of VEGF-C also trapped the VEGFR-2, VEGFR-3, CXCR4, CCR7-dependent axes, and down-regulated the AKT, ERK and p38 signalling pathways. These results suggest that VEGF-C has a multifaceted role in NSCLC growth, migration and invasion; that VEGF-C-mediated autocrine loops with their cognate receptors and chemokine receptors are significant factors affecting tumour progression; and that RNAi-mediated silencing of VEGF-C represents a powerful therapeutic approach for controlling NSCLC growth and metastasis.
血管内皮生长因子 C（VEGF-C）的表达与恶性肿瘤表型相关，使其成为有吸引力的治疗靶点。我们研究了 VEGF-C 在肿瘤生长、迁移和侵袭中的生物学作用，并探讨了 VEGF-C 作为治疗非小细胞肺癌（NSCLC）的潜在治疗靶点的可能性。我们使用慢病毒介导的 RNA 干扰（RNAi）技术特异性敲低 A549 细胞中 VEGF-C 的表达。使用定量逆转录聚合酶链反应、流式细胞术、Western blot、免疫组织化学、细胞生长、迁移、侵袭和 ELISA 检测来体外鉴定 VEGF-C 的表达。建立裸鼠肺癌异种移植模型，以研究敲低 VEGF-C 是否能减少体内肿瘤生长。沉默 VEGF-C 可抑制体外肿瘤细胞的生长、迁移和侵袭；通过尾静脉注射慢病毒编码的针对 VEGF-C 的 shRNA 可抑制体内肿瘤生长、血管生成和淋巴管生成。更重要的是，沉默 VEGF-C 还阻断了 VEGFR-2、VEGFR-3、CXCR4、CCR7 依赖性轴，并下调了 AKT、ERK 和 p38 信号通路。这些结果表明，VEGF-C 在 NSCLC 的生长、迁移和侵袭中具有多方面的作用；VEGF-C 介导的自分泌环及其同源受体和趋化因子受体是影响肿瘤进展的重要因素；RNAi 介导的 VEGF-C 沉默代表了控制 NSCLC 生长和转移的有效治疗方法。
