WISP-1, a novel angiogenic regulator of the CCN family, promotes oral squamous cell carcinoma angiogenesis through VEGF-A expression
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Jing-Yuan Chuang1,*, Po-Chun Chen2,3,*, Ching-Wen Tsao1, An-Chen Chang2, Ming-Yu Lein2,4, Ching-Chia Lin5, Shih-Wei Wang6, Chiao-Wen Lin7,8, Chih-Hsin Tang2,9,10
1Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan
2Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
3Department of Medical Research, Chung Shan Medical University Hospital, Chung Shan Medical University, Taichung, Taiwan
4Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
5Department of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan
6Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
7Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan
8Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
9Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan
10Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan
*These authors have contributed equally to this study
Chih-Hsin Tang, e-mail: [email protected]
Chiao-Wen Lin, e-mail: [email protected]
Keywords: WISP-1, VEGF-A, oral squamous cell carcinoma, angiogenesis
Received: September 23, 2014 Accepted: December 19, 2014 Published: January 30, 2015
Oral squamous cell carcinoma (OSCC), which accounts for nearly 90% of head and neck cancers, is characterized by poor prognosis and a low survival rate. VEGF-A is the most established angiogenic factor involved in the angiogenic-regulated tumor progression. WISP-1/CCN4 is an extracellular matrix-related protein that belongs to the Cyr61, CTGF, Nov (CCN) family and regulates many biological functions, such as angiogenesis. Previous studies indicated the role of WISP-1 in tumor progression. However, the angiogenic property of WISP-1 in the cancer microenvironment has never been discussed. Here, we provide novel insights regarding the role of WISP-1 in the angiogenesis through promoting VEGF-A expression. In this study, the correlation of WISP-1 and VEGF-A was confirmed by IHC staining of specimens from patients with OSCC. In vitro results indicated that WISP-1 induced VEGF-A expression via the integrin αvβ3/FAK/c-Src pathway, which transactivates the EGFR/ERK/HIF1-α signaling pathway in OSCC. This pathway in turn induces the recruitment of endothelial progenitor cells and triggers the neovascularization in the tumor microenvironment. Our in vivo data revealed that tumor-secreted WISP-1 promoted the angiogenesis through VRGF expression and increased angiogenesis-related tumor growth. Our study offers new information that highlights WISP-1 as a potential novel therapeutic target for OSCC.
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