Biglycan stimulates VEGF expression in endothelial cells by activating the TLR signaling pathway

Abstract

Biglycan (BGN) is an important component of the extracellular matrix (ECM) that is impli-cated in a variety of human cancers. In our previous study, we reported that BGN was overexpressed in gastric cancer (GC) tissues and promoted cancer metastasis. Moreover, the tubular formation capacity in HUVECs was promoted by stimulation with culture media from BGN-overexpressing GC cells, but the exact underlying mechanism is still unknown.The purpose of this study was to determine the role and molecular mechanism of BGN in VEGF expression in endothelial cells. We found that BGN stimulation of endothelial cells increased the interaction between NF-kB and the HIF-1a promoter, leading to enhanced promoter activity and increased HIF-1a mRNA levels, as well as augmented HIF-1 activity that resulted in VEGF expression. All of this was dependent on the interaction of BGN with its receptors, TLR2 and TLR4. Moreover, we found that BGN enhanced endothelial cell migration and proliferation, as well as tube formation, in a TLR signaling pathwaydependent manner. In addition, endothelial cell-derived VEGF in turn was found to act on GC cells and promotes their migration. The combined findings of our current and previous studies suggest that BGN secreted from GC cells into the tumor stroma promotes GC development, as well as its progression, potentially through the chronic activation of tumor angiogenesis. ª 2016 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. IntroductionGastric cancer (GC) poses a great threat to the health of people worldwide and ranks third among all types of tumors in China (Piazuelo and Correa, 2013). Therefore, it is of great importance to explore the mechanisms of the occurrence and development of GC. Studies have proven that tumor inflammation is a key component of the tumor microenvironment, which contributes to tumor proliferation, survival and invasion (Mantovani et al., 2008). The most important factor causing inflammation in GC may be Helicobacter pylori (HP) infections (Horemans et al., 2016;Kazemi et al., 2016;Liang et al., 2014), especially with HP containing a contiguous cag pathogenicity island (cag-PAI), which encodes a known virulence factor,

Role of TLR4‐MAP4K4 signaling pathway in models of oxygen‐induced retinopathy

“…Most of the literature suggests that the primary role of TLR4 in angiogenesis is to enhance VEGF expression (11,12,34,35,42). In our study, MAP4K4 was discovered working downstream of TLR4 in a VEGF-independent pattern and played a role in regulating migration and proliferation in HRMECs.…”

“…TLR4 is expressed in a diverse array of cells outside the immune system, and plays important roles in tissuespecific inflammation (28). TLR4 in endothelial cells contributes to angiogenesis as demonstrated in many systems, including sepsis-induced inflammatory angiogenesis in the lung (10), coculture systems of outgrowth endothelial cells and primary human osteoblasts (11), angiogenesis in cancer (12,13,33), rheumatoid arthritis (34), and recovery from brain injuries (35). TLR4 activation has reportedly resulted in ocular vascular abnormality.…”

“…Endothelial cells activated by ischemia can release inflammatory mediators such as cytokines and ligands for pattern recognition receptors (9). TLR4 activation in endothelial cells has been shown to promote inflammation-induced angiogenesis in a variety of settings (10)(11)(12)(13)(14). Downstream of TLR, MAPKK kinase kinase 4 (MAP4K4) plays a key role in inflammation and immune responses (15)(16)(17)(18).…”

BGN/TLR4/NF-κB Mediates Epigenetic Silencing of Immunosuppressive Siglec Ligands in Colon Cancer Cells

“…BGN is involved in various aspects of cancer biology, including cancer cell proliferation, invasion [38], epithelial-mesenchymal transition [39], angiogenesis [40], chemotherapy resistance [23], and patient prognosis [41], but the role of BGN during the early stages of cancer has not yet been elucidated. BGN expression is increased in many cancers including bladder cancer [39], colorectal cancer [42], gastric cancer [43], esophageal cancer [44], prostate cancer [40], and endometrial cancer [45] and various factors modulate its expression, including p38 [46], HIF-1 [47], TGF-β/Smad4 [48], and NF-κB [26]. NF-κB may serve a crucial factor at the early stage of colorectal cancer progression, and we demonstrated that it may play a crucial role in the regulation of BGN gene expression.…”

Molecular Dynamics of A Biglycan-Rosmarinic Acid Complex with Focal Adhesion Kinase for Possible Arrest of Metastasis in Non-Small Cell Lung Cancer (NSCLC): An In- Silico Study

“…Biglycan (BGN) is a member of small leucine-rich proteoglycans family, and it has been ascribed a pivotal role in oncogenesis and development of various other types of human cancer. It is also an important component of the extracellular matrix 9 . BGN is found in almost every organ in a non-uniform distribution pattern within human body.…”