Aberrant expression and association of VEGF and Dll4/Notch pathway molecules under hypoxia in patients with lung cancer.
Aberrant expression and association of VEGF and Dll4/Notch pathway molecules under hypoxia in patients with lung cancer.
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DOI：
10.14670/hh-28.277
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发表时间：
2013-02
影响因子：
2
通讯作者：
Shuang Yu;Jianhua Sun;Jingru Zhang;Xingfang Xu;Hong Li;Bao-zhong Shan;Tian Tian-Tian;Hongchun Wang
中科院分区：
文献类型：
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作者：
Shuang Yu;Jianhua Sun;Jingru Zhang;Xingfang Xu;Hong Li;Bao-zhong Shan;Tian Tian-Tian;Hongchun Wang
肿瘤血管生成在肺癌的发生和预后中起重要作用。血管内皮生长因子（VEGF）和Dll4/Notch通路对于血管生成都是至关重要的，然而它们在肺癌中缺氧下的关系仍然未知。因此，在本研究中，我们评估VEGF和Dll4/Notch信号分子的表达，并评估其与微血管密度（CD31）和缺氧（HIF 1a）在肺癌和正常肺组织中的关系，使用免疫组织化学和实时RT-PCR技术。然后，我们将Dll 4转染HUVECs，研究其生物学功能。在肺癌组织中，Notch通路分子（HES 1）和VEGF通路分子（VEGFR1和VEGFR2）表达显著上调，而VEGFR1/VEGFR2比值降低。CD31和HIF 1a在肺癌中也被发现升高。VEGFR1与Notch1呈负相关，与Dll4呈正相关。CD31与HIF 1a呈正相关，与VEGFR1呈负相关。肺癌组织中HIF 1a与HES 1表达呈正相关。转染后，与对照组相比，转染Dll4的HUVECs中Dll4、Notch1和VEGFR1表达上调，而VEGF和VEGFR2表达下调。VEGF和VEGFR2的表达随着肺癌的进展而逐渐增加。总之，VEGF和Notch信号通路分子在肺癌中过表达，这与缺氧（HIF 1a）和血管生成（CD 31）正相关。VEGF与Dll4/Notch信号通路在肺肿瘤血管生成中可能存在负反馈环。
Tumor angiogenesis plays important roles in the pathogenesis and prognosis of lung cancer. Both vascular endothelial growth factor (VEGF) and Dll4/Notch pathways are critical for angiogenesis, whereas their relationship under hypoxia in lung cancer remains unknown. Thus, in the present study, we evaluated the expression of VEGF and Dll4/Notch signaling molecules, and assessed their association with the microvessel density (CD31) and hypoxia (HIF1a) in lung cancer and normal lung tissues using immunohistochemical and Real-time RT-PCR techniques. Then, we investigated the biological function of Dll4 by transfecting Dll4 into HUVECs. In lung cancer tissues, Notch pathway molecules (HES1) and VEGF pathway molecules (VEGFR1 and VEGFR2) were significantly up-regulated, while the ratio of VEGFR1/VEGFR2 was decreased. CD31 and HIF1a were also found to be elevated in lung cancer. VEGFR1 was negatively correlated with Notch1 while positively correlated with Dll4. CD31 was positively correlated with HIF1a but negatively correlated with VEGFR1. Moreover, HIF1a was nearly positively correlated with HES1 in lung cancer tissues. After transfection, Dll4, Notch1 and VEGFR1 were up-regulated while VEGF and VEGFR2 were down-regulated in Dll4-transfected HUVECs compared with controls. Also, our findings suggest that the expression of VEGF and VEGFR2 increased gradually with the disease progression of lung cancer. In summary, VEGF and Notch signaling pathway molecules were overexpressed in lung cancer, which positively correlates with hypoxia (HIF1a) and angiogenesis (CD31). There might be a negative feedback loop between VEGF and Dll4/Notch signaling pathway in lung tumor angiogenesis.