GATA3-induced vWF upregulation in the lung adenocarcinoma vasculature

// Yinghua Xu 1, * , Silin Pan 2, * , Jing Liu 3 , Fengyun Dong 3 , Zuowang Cheng 1 , Jinjin Zhang 3 , Ruixia Qi 1 , Qi Zang 4 , Caiqing Zhang 5 , Xia Wang 3 , Jiandong Zhang 6 , Fufang Wang 7, 8 , Thaddeus D. Allen 9 and Ju Liu 3 1 Taishan Medical College, Tai’an, Shandong, China 2 Heart Center, Qingdao Women and Children’s Hospital, Qingdao University, Qingdao, Shandong, China 3 Laboratory of Microvascular Medicine, Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China 4 Department of Thoracic Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China 5 Department of Respiratory and Critical Care Medicine, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China 6 Department of Radiation Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China 7 Department of Geriatrics, Qilu Hospital of Shandong University, Jinan, Shandong, China 8 Key Laboratory of Cardiovascular Proteomics of Shandong Province, Jinan, Shandong, China 9 Tradewind BioScience, Daly City, CA, USA * These authors have contributed equally to this work Correspondence to: Ju Liu, email: ju.liu@sdu.edu.cn Keywords: lung adenocarcinoma; von Willebrand factor (vWF); vasculature; GATA3 Received: September 14, 2017      Accepted: November 13, 2017      Published: November 30, 2017 ABSTRACT Lung adenocarcinoma (LAC) is the leading cause of cancer-related death worldwide. Aberrant expression of genes expressed preferentially in the lung tumor vasculature may yield clues for prognosis and treatment. Von Willebrand factor (vWF) is a large multifunctional glycoprotein with a well-known function in hemostasis. However, vWF has been reported to exert an anti-tumor effect, independent of its role in hemostasis. We investigated the expression of vWF in LAC through immunohistochemical staining of tumor tissue microarrays (TMAs). We found that vWF was overexpressed preferentially in the tumor vasculature of LAC compared with the adjacent tissue vasculature. Consistently, elevated vWF expression was found in endothelial cells (ECs) of fresh human LAC tissues and transplanted mouse LAC tissues. To understand the mechanism underlying vWF up-regulation in LAC vessels, we established a co-culture system. In this system, conditioned media (CM) collected from A549 cells increased vWF expression in human umbilical vein endothelial cells (HUVECs), suggesting enhanced expression is regulated by the LAC secretome. Subsequent studies revealed that the transcription factor GATA3, but not ERG, a known regulator of vWF transcription in vascular cells, mediated the vWF elevation. Chromatin immunoprecipitation (ChIP) assays validated that GATA3 binds directly to the +220 GATA binding motif on the human vWF promoter and A549 conditioned media significantly increases the binding of GATA3. Taken together, we demonstrate that vWF expression in ECs of LAC is elevated by the cancer cell-derived secretome through enhanced GATA3-mediated transcription.