Leptin increases VEGF expression and enhances angiogenesis in human chondrosarcoma cells

Wei-Hung Yang; Jui-Chieh Chen; Kai-Hsiang Hsu; Chih-Yang Lin; Shih-Wei Wang; Shoou-Jyi Wang; Yung-Sen Chang; Chih-Hsin Tang

doi:10.1016/j.bbagen.2014.09.012

Leptin increases VEGF expression and enhances angiogenesis in human chondrosarcoma cells

Biochim Biophys Acta. 2014 Dec;1840(12):3483-93. doi: 10.1016/j.bbagen.2014.09.012. Epub 2014 Sep 16.

Authors

Wei-Hung Yang¹, Jui-Chieh Chen², Kai-Hsiang Hsu³, Chih-Yang Lin³, Shih-Wei Wang⁴, Shoou-Jyi Wang⁵, Yung-Sen Chang⁶, Chih-Hsin Tang⁷

Affiliations

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.

PMID: 25230157
DOI: 10.1016/j.bbagen.2014.09.012

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.

Keywords: Chondrosarcoma; Endothelial progenitor cells; Leptin; Tumor angiogenesis; VEGF.