Leptin promotes VEGF-C production and induces lymphangiogenesis by suppressing miR-27b in human chondrosarcoma cells.

Wei-Hung Yang,Shao-Keh Hsu,Tzu-Ming Chang,Shoou-Jyi Wang,Yi-Chin Fong,An-Chen Chang,Chih-Hsin Tang,Shih-Wei Wang,Yung-Sen Chang

doi:10.1038/srep28647

Abstract

Chondrosarcoma is the second most frequently occurring type of bone malignancy that is characterized by the distant metastasis propensity. Vascular endothelial growth factor-C (VEGF-C) is the chief lymphangiogenic mediator, and makes crucial contributions to tumor lymphangiogenesis. Leptin is an adipocytokine and has been indicated to facilitate tumorigenesis, angiogenesis and metastasis. However, the effect of leptin on VEGF-C regulation and lymphangiogenesis in human chondrosarcoma has hugely remained a mystery. Our results showed a clinical correlation between leptin and VEGF-C as well as tumor stage in human chondrosarcoma tissues. We further demonstrated that leptin promoted VEGF-C production and secretion in human chondrosarcoma cells. The conditioned medium from leptin-treated chondrosarcoma cells induced lymphangiogenesis of human lymphatic endothelial cells. We also found that leptin-induced VEGF-C is mediated by the FAK, PI3K and Akt signaling pathway. Furthermore, the expression of microRNA-27b was negatively regulated by leptin via the FAK, PI3K and Akt cascade. Our study is the first to describe the mechanism of leptin-promoted lymphangiogenesis by upregulating VEGF-C expression in chondrosarcomas. Thus, leptin could serve as a therapeutic target in chondrosarcoma metastasis and lymphangiogenesis.

Highlights

Is expressed in lymphatic endothelial cells (LECs)
We quantitated the IHC results and found the leptin and VEGF-C expression have high positive relationship in human chondrosarcoma patients (Fig. 1C). These results suggest that leptin is strongly associated with VEGF-C expression and tumor stage in chondrosarcoma patients
Accumulating evidences demonstrate that increased levels of VEGF-C promotes tumor relapse and poor prognosis, and VEGF-C represents a potential target for preventing lymphatic metastasis[6,15]

Summary

Introduction

Is expressed in lymphatic endothelial cells (LECs). The VEGF-C and VERFR-3 interaction has been reported to mediate LECs proliferation, survival, migration and tube formation during lymphangiogenic process[9]. MiR-128 has been reported to inhibit lymphangiogenesis in human lung cancer cells by directly suppressing VEGF-C expression. We previously reported that leptin enhances cell migration through activation of integrin αvβ[3] and increases VEGF-A-dependent tumor angiogenesis in human chondrosarcoma[30,31], implying that leptin is involved in the metastasis of chondrosarcoma. It is still not well-recognized whether leptin increases VEGF-C expression to facilitate tumor-associated lymphangiogenesis in human chondrosarcoma. We examined the effect of leptin in VEGF-C-mediated lymphangiogenesis, and evaluated the involvement of miRNA in human chondrosarcoma cells

Methods

Results

Conclusion