Angiotensin II induces vascular endothelial growth factor in pancreatic cancer cells through an angiotensin II type 1 receptor and ERK1/2 signaling
Angiotensin II induces vascular endothelial growth factor in pancreatic cancer cells through an angiotensin II type 1 receptor and ERK1/2 signaling
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DOI：
10.1007/s11605-007-0403-9
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发表时间：
2008-01-01
影响因子：
3.2
通讯作者：
Arafat, Hwyda A.
中科院分区：
文献类型：
--
作者：
Anandanadesan, Rathai;Gong, Qiaoke;Arafat, Hwyda A.
血管内皮生长因子(VEGF)是胰腺导管腺癌(PDA)中重要的促血管生成成分，其高表达水平与预后不良及术后早期复发密切相关。我们最近发现，侵袭性PDA中高水平的血管紧张素II(AngII)1型受体(AT1R)与血管内皮生长因子(VEGF)相关并共存，并且血管紧张素II诱导PDA细胞系中血管内皮生长因子的表达。在这项研究中，我们探讨了血管紧张素Ⅱ介导的血管内皮生长因子诱导的信号机制，以及AT1R和血管内皮生长因子在非侵袭性前体病变中的表达。AT1R拮抗剂显著抑制血管紧张素Ⅱ介导的血管内皮生长因子信使RNA和蛋白在所有PDA细胞系中的诱导。酪氨酸激酶抑制剂金雀异黄素可抑制血管内皮生长因子的诱导，提示有丝分裂原激活的蛋白激酶信号转导机制。Angii可激活细胞外信号调节激酶1/2(ERK1/2)的磷酸化，但不能激活p38或c-jun NH2末端的MAP激酶。抑制ERK1/2的激活可减少血管紧张素Ⅱ诱导的血管内皮生长因子的合成。前驱病变的免疫组织化学分析显示，AT1R在大多数发生化生的导管细胞中表达增加。胰腺上皮内肿瘤与导管内乳头状黏液性肿瘤相比，AT1R染色更强，后者表现出不同程度的免疫反应。血管内皮生长因子在两种病变中的分布规律相同。AT1R在胰腺癌前病变中的表达提示其参与了肿瘤的进展和血管生成。我们的机制发现提供了第一次洞察血管紧张素Ⅱ启动的调节PDA血管生成的信号通路。AT1R介导的血管内皮生长因子的诱导提示了AT1R阻断作为一种控制PDA血管生成的新的治疗策略的可能性。
Vascular endothelial growth factor (VEGF) is a crucial pro-angiogenic component in pancreatic ductal adenocarcinoma (PDA), and its high expression levels have been correlated with poor prognosis and early postoperative recurrence. We have recently shown that high levels of angiotensin II (AngII) type 1 receptor (AT1R) correlate and colocalize with VEGF in invasive PDA and that AngII induces VEGF expression in PDA cell lines. In this study, we explored the signaling mechanisms involved in the AngII-mediated VEGF induction and correlated AT1R and VEGF expression in noninvasive precursor lesions. An AT1R antagonist significantly (p < 0.05) inhibited the AngII-mediated induction of VEGF messenger RNA and protein in all PDA cell lines. AngII-VEGF induction was inhibited by the tyrosine kinase inhibitor genistein, suggesting a mitogen-activated protein kinase signaling mechanism. AngII activated the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), but not p38 or c-Jun NH2-terminal MAP kinases. Inhibition of ERK1/2 activation reduced the AngII-induced VEGF synthesis. Immunohistochemical analysis of precursor lesions showed increased expression of AT1R in most ductal cells undergoing metaplasia. Pancreatic intraepithelial neoplasms showed more intense AT1R staining when compared to intraductal papillary mucinous neoplasms, which showed heterogeneous immunoreactivity. VEGF followed the same distribution pattern of AT1R in both lesions. AT1R expression in the premalignant pancreatic lesions suggests its involvement in tumor progression and angiogenesis. Our mechanistic findings provide the first insight into an AngII-initiated signaling pathway that regulates PDA angiogenesis. An AT1R-mediated VEGF induction suggests the possibility of AT1R blockade as a novel therapeutic strategy to control angiogenesis in PDA.