GATA3-induced vWF upregulation in the lung adenocarcinoma vasculature

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.

Lmo4‐resistin signaling contributes to adipose tissue‐liver crosstalk upon weight cycling

“…We observed a significant increase in the number of blood vessels (αSMA + cells) in HF mice compared to LF mice, and this number was further increased in HF‐LF cycled mice (Figure E). Moreover, HF‐LF cycled mice exhibited increased mRNA levels of angiogenic factors such as Vegfa (vascular endothelial growth factor A) and Vwf (von Willebrand factor), but not Vegfb , compared to those of HF and LF mice (Figure F).…”

“…n = 3-6 per group. *P < .05 compared with LF group; # P < .05 compared with HF group factors such as Vegfa (vascular endothelial growth factor A 33 ) and Vwf (von Willebrand factor 34 ), but not Vegfb, compared to those of HF and LF mice ( Figure 3F).…”

GATA3 is downregulated in osteosarcoma and facilitates EMT as well as migration through regulation of slug

“…Accumulating evidence has shown that GATA3 play key roles in cancer development. 28 – 30 Here, we first revealed that GATA3 was downregulated in OS. CCK-8 assay and colony formation assay demonstrated that GATA3 inhibited OS cells proliferation.…”

Prognostic value of plasma von Willebrand factor levels in major adverse cardiovascular events: a systematic review and meta-analysis

“…Together, our results suggested that plasma level of vWF is an indicator for the risk of MACEs among patients with CAD. vWF is mainly synthesized in endothelial cells [25,26]. Upon endothelial cell injury, vWF is released into the blood circulation.…”