Oncotarget

Research Papers:

GATA3-induced vWF upregulation in the lung adenocarcinoma vasculature

Yinghua Xu, Silin Pan, Jing Liu, Fengyun Dong, Zuowang Cheng, Jinjin Zhang, Ruixia Qi, Qi Zang, Caiqing Zhang, Xia Wang, Jiandong Zhang, Fufang Wang, Thaddeus D. Allen and Ju Liu _

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Oncotarget. 2017; 8:110517-110529. https://doi.org/10.18632/oncotarget.22806

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Abstract

Yinghua Xu1,*, Silin Pan2,*, Jing Liu3, Fengyun Dong3, Zuowang Cheng1, Jinjin Zhang3, Ruixia Qi1, Qi Zang4, Caiqing Zhang5, Xia Wang3, Jiandong Zhang6, Fufang Wang7,8, Thaddeus D. Allen9 and Ju Liu3

1Taishan Medical College, Tai’an, Shandong, China

2Heart Center, Qingdao Women and Children’s Hospital, Qingdao University, Qingdao, Shandong, China

3Laboratory of Microvascular Medicine, Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China

4Department of Thoracic Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China

5Department of Respiratory and Critical Care Medicine, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China

6Department of Radiation Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China

7Department of Geriatrics, Qilu Hospital of Shandong University, Jinan, Shandong, China

8Key Laboratory of Cardiovascular Proteomics of Shandong Province, Jinan, Shandong, China

9Tradewind 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.


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