title: 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 implicated 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-1α promoter, leading to enhanced promoter activity and increased HIF-1α 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 pathway-dependent 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.
authors: Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China.
authors: Lei
authors: L
authors: Hu
authors: Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China.
authors: Ming-de
authors: MD
authors: Zang
authors: Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China.
authors: He-Xiao
authors: HX
authors: Wang
authors: Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China.
authors: Jian-Fang
authors: JF
authors: Li
authors: Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China.
authors: Li-Ping
authors: LP
authors: Su
authors: Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China.
authors: Min
authors: M
authors: Yan
authors: Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China.
authors: Chen
authors: C
authors: Li
authors: Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China.
authors: Qiu-Meng
authors: QM
authors: Yang
authors: Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China. Electronic address: liubingya@sjtu.edu.cn.
authors: Bing-Ya
authors: BY
authors: Liu
authors: Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China. Electronic address: zzg1954@hotmail.com.
authors: Zheng-Gang
authors: ZG
authors: Zhu
mesh_terms: D058578:Biglycan / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology; D051193:Toll-Like Receptors / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D058578:Biglycan; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D011994:Recombinant Proteins; D051193:Toll-Like Receptors; D042461:Vascular Endothelial Growth Factor A
keywords: Angiogenesis; BGN; Endothelial cells; GC; TLR2/4; VEGF