Vascular endothelial growth factor receptor-1 activation mediates epithelial to mesenchymal transition in human pancreatic carcinoma cells
Vascular endothelial growth factor receptor-1 activation mediates epithelial to mesenchymal transition in human pancreatic carcinoma cells
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DOI：
10.1158/0008-5472.can-05-3086
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发表时间：
2006-01-01
期刊：
影响因子：
11.2
通讯作者：
Ellis, LM
中科院分区：
文献类型：
--
作者：
Yang, AD;Camp, ER;Ellis, LM
我们的实验室已经证明血管内皮生长因子受体-1 （VEGFR-1）在人胰腺癌细胞系上的表达介导细胞迁移和侵袭。由于上皮到间充质转化（EMT）也通过改变细胞表型和形态在细胞运动中起作用，我们假设VEGFR-1激活诱导介导EMT的分子改变。我们用VEGFR-1配体VEGF-A和VEGF-B处理人胰腺癌细胞系L3.6pl，导致EMT特征的形态学改变，包括极性丧失、细胞间分离增加和假足的存在。E-cadherin和β -catenin抗体的免疫荧光染色显示，VEGFR-1激活导致E-cadherin和β -catenin分别从其通常的细胞膜结合位置易位到细胞质和细胞核。Western blotting结果显示，VEGFR-1激活导致上皮标记物E-cadherin和血小板红蛋白表达降低，间质标记物vimentin和N-cadherin表达增加，细胞核β -catenin表达增加。用VEGFR-1阻断抗体预处理肿瘤细胞可抑制VEGFR-1诱导的E-cadherin免疫组织化学和分子变化。VEGFR-1激活导致emt相关转录因子Snail、Twist和Slug的表达增加。VEGFR-1在该胰腺癌细胞系中介导的变化与EMT的变化特征高度一致。鉴于我们之前在胰腺癌细胞中发现VEGFR-1介导肿瘤细胞的侵袭和迁移，我们假设VEGFR-1通过诱导EMT在胰腺癌的肿瘤进展中发挥作用。
Our laboratory has shown that vascular endothelial growth factor receptor-1 (VEGFR-1) expression on human pancreatic cancer cell lines mediates cell migration and invasion. Because epithelial to mesenchymal transition (EMT) also plays a role in cell motility by altering the cell phenotype and morphology, we hypothesized that VEGFR-1 activation induces molecular alterations that mediate EMT. Our treatment of the human pancreatic cancer cell line L3.6pl with the VEGFR-1 ligands VEGF-A and VEGF-B led to morphologic changes characteristic of EMT, including loss of polarity, increased intercellular separation, and the presence of pseudopodia. Immunofluorescent staining with antibodies to E-cadherin and beta-catenin showed that VEGFR-1 activation led to translocation of E-cadherin and beta-catenin from their usual cell membrane-bound location to the cytoplasm and nucleus, respectively. Western blotting showed that VEGFR-1 activation led to decreased expression of the epithelial markers E-cadherin and plakoglobin, increased expression of the mesenchymal markers vimentin and N-cadherin, and increased nuclear expression of beta-catenin. Pretreatment of tumor cells with a VEGFR-1 blocking antibody inhibited the VEGFR-1-induced inummohistochemical and molecular changes in E-cadherin. VEGFR-1 activation led to an increase in expression of the EMT-associated transcription factors Snail, Twist, and Slug. The changes mediated by VEGFR-1 in this pancreatic carcinoma cell line are highly consistent with the changes characteristic of EMT. Given our previous finding of VEGFR-1-mediated tumor cell invasion and migration in pancreatic carcinoma cells, we hypothesize that VEGFR-1 plays a role in tumor progression in pancreatic cancer through the induction of EMT.