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

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

doi:10.18632/oncotarget.7014

Abstract

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.

Highlights

Oral squamous cell carcinoma (OSCC) represents 1–2% of all human malignancies and is the most prevalent type of oral cancer [1, 2]
Quantitative data showed that WNT1-inducible signaling pathway protein-1 (WISP)-1 expression was correlated with Vascular endothelial growth factor-C (VEGF-C) expression in human OSCC specimens (Figure 1E), indicating that WISP-1 is associated with VEGF-C expression and tumor stage in patients with OSCC
VEGF-C is a key modulator in tumor lymphangiogenesis and metastasis, and VEGF-C is a potential target for preventing tumor lymphatic metastasis

Summary

Introduction

Oral squamous cell carcinoma (OSCC) represents 1–2% of all human malignancies and is the most prevalent type of oral cancer [1, 2]. 50% of patients with OSCC present with lymph node metastasis at the time of diagnosis. OSCC has a poor prognosis and a low survival rate [3]. The current 5-year survival rate is approximately 50% because the available therapies are inadequate [4]. Investigating how to reduce invasion and metastasis in OSCC may facilitate the development of effective adjuvant therapies. The metastatic spread of tumor cells is associated with resistance to conventional therapies and is the leading cause of death for cancer patients. Tumor metastasis comprises many processes, such as proliferation [5], migration [6], invasion [7], angiogenesis [8], and lymphangiogenesis [9]. Lymphangiogenesis is a key step during tumor metastasis

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Results

Conclusion