WISP-1 a novel angiogenic regulator of the CCN family promotes oral squamous cell carcinoma angiogenesis through VEGF-A expression.
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.
Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan.
Jing-Yuan
JY
Chuang
Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.|Department of Medical Research, Chung Shan Medical University Hospital, Chung Shan Medical University, Taichung, Taiwan.
Po-Chun
PC
Chen
Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan.
Ching-Wen
CW
Tsao
Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
An-Chen
AC
Chang
Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.|Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.
Ming-Yu
MY
Lein
Department of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan.
Ching-Chia
CC
Lin
Department of Medicine, Mackay Medical College, New Taipei City, Taiwan.
Shih-Wei
SW
Wang
Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan.|Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan.
Chiao-Wen
CW
Lin
Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.|Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan.|Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan.
Chih-Hsin
CH
Tang
D000818:Animals; D055511:CCN Intercellular Signaling Proteins / Q000235:genetics* / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D006258:Head and Neck Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D009062:Mouth Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D000077195:Squamous Cell Carcinoma of Head and Neck; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D055511:CCN Intercellular Signaling Proteins; C116396:CCN4 protein, human; D011518:Proto-Oncogene Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A