Integrin alpha x stimulates cancer angiogenesis through PI3K/Akt signaling-mediated VEGFR2/VEGF-A overexpression in blood vessel endothelial cells
Integrin alpha x stimulates cancer angiogenesis through PI3K/Akt signaling-mediated VEGFR2/VEGF-A overexpression in blood vessel endothelial cells
复制标题
整合素αx通过血管内皮细胞中PI3K/Akt信号介导的VEGFR2/VEGF-A过度表达刺激癌症血管生成
DOI：
10.1002/jcb.27480
复制
发表时间：
2019-02-01
影响因子：
4
通讯作者：
Yang, Gong
中科院分区：
文献类型：
--
作者：
Wang, Jingshu;Yang, Lina;Yang, Gong
整合素αx(ITGAX)是整合素家族的一员，通常作为细胞外基质的受体。最近，越来越多的证据表明，ITGAX可能参与了树突状细胞的血管生成。在此，我们报告了ITGAX在肿瘤发展过程中对血管生成的直接作用。ITGAX在人脐静脉内皮细胞(HUVECs)中的过表达促进了其增殖、迁移和管状形成，并促进了移植卵巢肿瘤的血管生成和生长。进一步研究表明，ITGAX的过表达激活了PI3K/Akt通路，导致c-Myc、血管内皮生长因子-A(VEGF-A)和血管内皮生长因子受体2(VEGFR2)的表达增强，而PI3K抑制剂处理细胞后，这些作用减弱。此外，还观察到c-Myc与血管内皮生长因子-A启动子结合。通过免疫共沉淀(Co-IP)实验，我们证实了ITGAX与VEGFR2或磷酸化VEGFR2的相互作用。免疫组织化学染色显示，卵巢癌微血管内皮细胞表达VEGF-A、c-Myc、VEGFR2和PI3K信号分子。此外，ITGAX在人脐静脉内皮细胞中的过表达可刺激卵巢癌细胞的球体形成。我们的研究发现，ITGAX通过PI3K/Akt信号介导的VEGFR2/VEGF-A在肿瘤发展过程中过度表达来刺激血管生成。
Integrin alpha x (ITGAX), a member of theintegrin family, usually serves as a receptor of the extracellular matrix. Recently, accumulating evidence suggests that ITGAX may be involved in angiogenesis in dendritic cells. Herein, we report a direct role of ITGAX in angiogenesis during tumor development. Overexpression of ITGAX in human umbilical vein endothelial cells (HUVECs) enhanced their proliferation, migration, and tube formation and promoted xenograft ovarian tumor angiogenesis and growth. Further study showed that overexpression of ITGAX activated the PI3k/Akt pathway, leading to the enhanced expression of c-Myc, vascular endothelial growth factor-A (VEGF-A), and VEGF receptor 2 (VEGFR2), whereas, the treatment of cells with PI3K inhibitor diminished these effects. Besides, c-Myc was observed to bind to the VEGF-A promoter. By Co-Immunoprecipitation (Co-IP) assay, we manifested the interaction between ITGAX and VEGFR2 or the phosphorylated VEGFR2. Immunostaining of human ovarian cancer specimens suggested that endothelial cells of micro-blood vessels displayed strong expression of VEGF-A, c-Myc, VEGFR2, and the PI3K signaling molecules. Also, overexpression of ITGAX in HUVECs could stimulate the spheroid formation of ovarian cancer cells. Our study uncovered that ITGAX stimulates angiogenesis through the PI3K/Akt signaling-mediated VEGFR2/VEGF-A overexpression during cancer development.