Research Papers:

WISP-1 promotes VEGF-C-dependent lymphangiogenesis by inhibiting miR-300 in human oral squamous cell carcinoma cells

Ching-Chia Lin, Po-Chun Chen, Ming-Yu Lein, Ching-Wen Tsao, Chiu-Chen Huang, Shih-Wei Wang, Chih-Hsin Tang and Kwong-Chung Tung _

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Oncotarget. 2016; 7:9993-10005. https://doi.org/10.18632/oncotarget.7014

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Ching-Chia Lin1, Po-Chun Chen2,3, Ming-Yu Lein2,4, Ching-Wen Tsao2, Chiu-Chen Huang5, Shih-Wei Wang6, Chih-Hsin Tang2,7,8, Kwong-Chung Tung1

1Department of Veterinary Medicine, National Chung Hsing 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

5Sing Wang Animal Hospital, Taichung, Taiwan

6Department of Medicine, Mackay Medical College, New Taipei City, Taiwan

7Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan

8Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan

Correspondence to:

Kwong-Chung Tung, e-mail: [email protected]

Chih-Hsin Tang, e-mail: [email protected]

Keywords: WISP-1, OSCC, lymphangiogenesis, VEGF-C, miR-300

Received: August 12, 2015     Accepted: January 01, 2016     Published: January 25, 2016


Oral squamous cell carcinoma (OSCC), which accounts for nearly 90% of head and neck cancers, is characterized by a poor prognosis and a low survival rate. Vascular endothelial growth factor-C (VEGF-C) has been implicated in lymphangiogenesis and is correlated with cancer metastasis. WNT1-inducible signaling pathway protein-1 (WISP)-1/CCN4 is an extracellular matrix-related protein that belongs to the CCN family and stimulates many biological functions. Our previous studies showed that WISP-1 plays an important role in OSCC migration and angiogenesis. However, the effect of WISP-1 on VEGF-C regulation and lymphangiogenesis in OSCC is poorly understood. Here, we showed a correlation between WISP-1 and VEGF-C in tissue specimens from patients with OSCC. To examine the lymphangiogenic effect of WISP-1, we used human lymphatic endothelial cells (LECs) to mimic lymphatic vessel formation. The results showed that conditioned media from WISP-1-treated OSCC cells promoted tube formation and cell migration in LECs. We also found that WISP-1-induced VEGF-C is mediated via the integrin αvβ3/integrin-linked kinase (ILK)/Akt signaling pathway. In addition, the expression of microRNA-300 (miR-300) was inhibited by WISP-1 via the integrin αvβ3/ILK/Akt cascade. Collectively, these results reveal the detailed mechanism by which WISP-1 promotes lymphangiogenesis via upregulation of VEGF-C expression in OSCC. Therefore, WISP-1 could serve as therapeutic target to prevent metastasis and lymphangiogenesis in OSCC.

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