Wei-Hung Yang1, Jui-Chieh Chen2, Kai-Hsiang Hsu3, Chih-Yang Lin3, Shih-Wei Wang4, Shoou-Jyi Wang5, Yung-Sen Chang6, Chih-Hsin Tang7. 1. Department of Orthopedic Surgery, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan; School of Chinese Medicine, China Medical University, Taichung, Taiwan; Department of Nursing, National Taichung University of Science and Technology, Taichung, Taiwan; Graduate Institute of Biotechnology, National Chung Hsing University, Taichung, Taiwan. 2. Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan; Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan. 3. Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan. 4. Department of Medicine, Mackay Medical College, New Taipei City, Taiwan. 5. Department of Orthopedic Surgery, Chang-Hua Hospital, Ministry of Health and Welfare, Puhsin Township, Changhua County, Taiwan. 6. Department of Orthopedic Surgery, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan. 7. 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. Electronic address: chtang@mail.cmu.edu.tw.
Abstract
BACKGROUND: Leptin, 16kDa product of obese gene, is adipocytokine playing critical role in regulation of body weight. In recent years, leptin is also defined as potent angiogenic factor involving in tumorigenesis, angiogenesis, and metastasis. However, it is unknown whether leptin regulates VEGF production in human chondrosarcoma and contributing the tumor-associated angiogenesis. METHODS: We analyzed protein level of leptin and VEGF in human chondrosarcoma tissues. Effects of leptin on chondrosarcoma cells were examined by in vitro and in vivo assays. In addition, intracellular signal pathways were investigated by pharmacological and genetic approaches. RESULTS: We found that both leptin and VEGF are highly expressed in human chondrosarcoma tissues, and positively correlated with tumor stage. Leptin increases VEGF production by activating OBRl receptor and MAPKs (p38, ERK, and JNK), which in turn enhances binding of AP-1 transcription factor to VEGF promoter, resulting in the transactivation of VEGF expression and subsequently promoting migration and tube formation in endothelial progenitor cells (EPCs). In vivo, knockdown leptin significantly reduces angiogenesis and tumor growth. CONCLUSION: Leptin may be a therapeutic target of angiogenesis and metastasis in chondrosarcoma. GENERAL SIGNIFICANCE: These findings provide better understanding of pathogenesis of chondrosarcoma and can utilize this knowledge to design new therapeutic strategy.
BACKGROUND:Leptin, 16kDa product of obese gene, is adipocytokine playing critical role in regulation of body weight. In recent years, leptin is also defined as potent angiogenic factor involving in tumorigenesis, angiogenesis, and metastasis. However, it is unknown whether leptin regulates VEGF production in humanchondrosarcoma and contributing the tumor-associated angiogenesis. METHODS: We analyzed protein level of leptin and VEGF in humanchondrosarcoma tissues. Effects of leptin on chondrosarcoma cells were examined by in vitro and in vivo assays. In addition, intracellular signal pathways were investigated by pharmacological and genetic approaches. RESULTS: We found that both leptin and VEGF are highly expressed in humanchondrosarcoma tissues, and positively correlated with tumor stage. Leptin increases VEGF production by activating OBRl receptor and MAPKs (p38, ERK, and JNK), which in turn enhances binding of AP-1 transcription factor to VEGF promoter, resulting in the transactivation of VEGF expression and subsequently promoting migration and tube formation in endothelial progenitor cells (EPCs). In vivo, knockdown leptin significantly reduces angiogenesis and tumor growth. CONCLUSION:Leptin may be a therapeutic target of angiogenesis and metastasis in chondrosarcoma. GENERAL SIGNIFICANCE: These findings provide better understanding of pathogenesis of chondrosarcoma and can utilize this knowledge to design new therapeutic strategy.
Authors: Federica Riu; Sadie C Slater; Eva Jover Garcia; Iker Rodriguez-Arabaolaza; Valeria Alvino; Elisa Avolio; Giuseppe Mangialardi; Andrea Cordaro; Simon Satchell; Carlo Zebele; Andrea Caporali; Gianni Angelini; Paolo Madeddu Journal: Sci Rep Date: 2017-07-14 Impact factor: 4.379