Research Papers:

Thrombomodulin promotes focal adhesion kinase activation and contributes to angiogenesis by binding to fibronectin

Yun-Yan Hsu, Guey-Yueh Shi, Kuan-Chieh Wang, Chih-Yuan Ma, Tsung-Lin Cheng, Hua-Lin Wu _

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Oncotarget. 2016; 7:68122-68139. https://doi.org/10.18632/oncotarget.11828

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Yun-Yan Hsu1, Guey-Yueh Shi1,2, Kuan-Chieh Wang1, Chih-Yuan Ma1, Tsung-Lin Cheng3,4, Hua-Lin Wu1,2

1Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

2Cardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, Taiwan

3Department of Physiology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

4Orthopaedic Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

Correspondence to:

Hua-Lin Wu, email: halnwu@mail.ncku.edu.tw

Keywords: endothelial cells, VEGF, thrombomodulin, fibronectin, angiogenesis

Received: December 10, 2015     Accepted: August 27, 2016     Published: September 02, 2016


Angiogenesis promotes tumor growth and metastasis. Cell adhesion molecules interact with the extracellular matrix (ECM) and increase cell adhesion and migration during angiogenesis. Thrombomodulin (TM) is a cell surface transmembrane glycoprotein expressed in endothelial cells. However, the function and significance of TM in cell-matrix interactions and angiogenesis remain unclear. Here, we first demonstrated that recombinant lectin-like domain of TM interacts with an ECM protein, fibronectin, and identified the N-terminal 70-kDa domain of fibronectin as the TM-binding site. Exogenous expression of TM in TM-deficient A2058 melanoma cells enhanced cell adhesion and migration on fibronectin and invasion on Matrigel. In addition, TM increased focal adhesion kinase (FAK) phosphorylation and matrix metalloproteinase-9 production. In mice bearing subcutaneous B16F10 melanoma tumors, immunofluorescence analysis indicated that TM was highly expressed and co-localized with fibronectin on the tumor vasculature. The interaction between TM and fibronectin in tumor blood vessels was also validated by the proximity ligation assay. In human umbilical vein endothelial cells, up-regulation of TM by vascular endothelial growth factor (VEGF), a tumor angiogenic factor, promoted cell adhesion and tube formation, whereas TM knockdown by RNA interference attenuated VEGF-induced cell adhesion and tube formation. In summary, TM promotes angiogenesis by enhancing cell adhesion, migration, and FAK activation through interaction with fibronectin. TM may represent a novel target for inhibiting tumor angiogenesis.

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