Leptin increases VEGF expression and enhances angiogenesis in human chondrosarcoma cells Yi-Chin Fong1,2*,Wei-Hung Yang3,4,5,6, Jui-Chieh Chen7,8, Chih-Hsin Tang7,9,10*
1
School of Chinese Medicine, China Medical University, Taichung, Taiwan
2
Department of Orthopaedics, China Medical University Hospital, Taichung, Taiwan
3
Department of Orthopedic Surgery, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan.
4
School of Chinese Medicine, China Medical University, Taichung, Taiwan
5
Department of Nursing, National Taichung University of Science and Technology, Taichung, Taiwan
6
Graduate Institute of Biotechnology, National Chung Hsing University, Taichung, Taiwan
7
Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
8
National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan
9
School of Medicine, China Medical University, Taichung, Taiwan
10
Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan
Abstract
Leptin, a 16 kDa product of the obese gene, is an adipocytokine that plays a critical role in the regulation of body weight. In recent years, leptin is also defined as a potent angiogenic factor, which is involved in tumorigenesis, angiogenesis, and metastasis. However, it is unknown whether leptin regulates VEGF production in human chondrosarcoma and contributing the tumor-associated angiogenesis. In the present study, we found that both leptin and VEGF are highly expressed in human chondrosarcoma tissues, which are positively correlated with histopathological grade. Thus, we examined the effects of exogenous leptin on chondrosarcoma cells. In addition, the intracellular signaling pathways were also investigated by pharmacological and genetic approaches. Our data show that leptin increases VEGF production by activating OBRl receptor and MAPKs (p38, ERK, and JNK), which in turn enhances the binding of AP-1 transcription factor to the VEGF promoter, resulting in the transactivation of VEGF expression and subsequently promoting migration and tube formation in endothelial progenitor cells (EPC). Further, we have also evaluated the effect of leptin on angiogenesis and tumor growth using the in vivo models. The results show that knockdown of leptin attenuates neovessel formation and arrests chondrosarcoma tumor growth in vivo. These findings may provide a better understanding of the pathogenesis of chondrosarcoma and can utilize this knowledge to design a new therapeutic strategy.
