Aberrant expression and association of VEGF and Dll4/Notch pathway molecules under hypoxia in patients with lung cancer
Shuang Yu1*, Jianhua Sun1,2*, Jingru Zhang1*, Xingfang Xu3, Hong Li4, Baozhong Shan5, Tian Tian1, Hongchun Wang1, Daoxin Ma1* and Chunyan Ji1
1Department of Hematology, Qilu Hospital, Shandong University, Jinan, 2Department of Cancer, The Second Hospital of Shandong University, Jinan, PRC, 3Department of Internal Medicine, Qihe County hospital, Qihe, PR China, 4Department of Physical Examination Center, Jinan Central Hospital Affiliated to Shandong University, Jinan, PRC and 5Department of Stomatology, Jinan Central Hospital Affiliated to Shandong University, Jinan, PRC
*These authors contributed equally to this work.
Offprint requests to: Daoxin Ma, Ph.D., M.D., Associate Professor. Department of Hematology, Qilu Hospital, Shandong University, 107 WenhuaXi Road, Jinan 250012, PRC. e-mail: daoxinma@sdu.edu.cn
Summary. 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. Histol Histopathol 28, 277-284 (2013)
Key words: VEGF, Dll4, Notch, Angiogenesis, Lung cancer
DOI: 10.14670/HH-28.277