Development of molecular target therapy to VEGF and VEGFR against oral cancer with RNAi methods

细胞迁移在肿瘤的侵袭和转移中起重要作用。本课题组前期研究发现血管内皮生长因子（VEGF）及其受体1（Flt-1）在口腔鳞癌细胞中表达。这些结果提示VEGF-VEGFR系统可能以自分泌方式调节血管生成，同时也可能以旁分泌方式调节血管生成。VEGF和VEGFR参与了黑色素瘤细胞的侵袭和转移，VEGFR-1反义寡核苷酸能抑制VEGF诱导的黑色素瘤细胞的增殖，而VEGFR-2反义寡核苷酸则不能抑制VEGF诱导的黑色素瘤细胞的增殖。VEGFR酪氨酸激酶抑制剂可抑制VEGF诱导的细胞迁移。VEGFR-1反义寡核苷酸可抑制Akt的迁移，而VEGFR-2反义寡核苷酸则不能抑制Akt的迁移。PI 3激酶抑制剂阻断VEGF诱导的PI 3/Akt激酶级联的磷酸化，并抑制VEGF诱导的黑素瘤细胞运动。这些发现表明，黑色素瘤细胞的迁移受VEGF诱导的PI 3/Akt激酶级联激活的调节

Cell migration plays a significant role in cancer invasion and metastasis. Our previous studies have shown vascular endothelial growth factor ( VEGF) and VEGF receptor 1 ( Flt-1 ) express in oral squamous cell carcinoma ( SCC ) cells. These finding suggests VEGF-VEGFR system might regulate in autocrine manner as well as angiogenesis in paracrine manner.In this study, we examined the expression of VEGF and VEGFR in melanoma cells. The participation of VEGF and VEGFR in invasion and metastasis of melanoma cells was also investigated.VEGF-induced proliferation of melanoma cells were suppressed by VEGFR-1 antisense oligo, but not by VEGFR-2 antisense oligo.Checkerbord analysis showed that VEGF induced Chemotaxitic and Chemokinetic migration in melanoma cells. The VEGF-induced migration was inhibited by VEGFR tyrosine kinase inhibitor. The migration was suppressed by VEGFR-1 antisense oligo, but not by VEGFR-2 antisense oligo.VEGF induced phosphorilation of Akt. PI3 kinase inhibitor block the VEGF-induced phosphorilation of PI3/Akt kinase cascade, and suppressed VEGF-induced motility of melanoma cells. These findings suggest that migration of melanoma cells is regulated with VEGF-induced activation of PI3/Akt kinase cascade