title: Leptin promotes VEGF-C production and induces lymphangiogenesis by suppressing miR-27b in human chondrosarcoma cells.
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.
authors.affiliation: 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.
authors.forename: Wei-Hung
authors.initials: WH
authors.lastname: Yang
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: An-Chen
authors.initials: AC
authors.lastname: Chang
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei City, Taiwan.
authors.forename: Shih-Wei
authors.initials: SW
authors.lastname: Wang
authors.affiliation: Department of Orthopedic Surgery, Chang-Hua Hospital, Ministry of Health and Welfare, Puhsin Township, Changhua County, Taiwan.
authors.forename: Shoou-Jyi
authors.initials: SJ
authors.lastname: Wang
authors.affiliation: Department of Orthopedic Surgery, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan.
authors.forename: Yung-Sen
authors.initials: YS
authors.lastname: Chang
authors.affiliation: Department of Orthopedic Surgery, Tungs' Taichung Metroharbor Hospital, Taichung, Taiwan.
authors.forename: Tzu-Ming
authors.initials: TM
authors.lastname: Chang
authors.affiliation: Department of Orthopedic Surgery, Tungs' Taichung Metroharbor Hospital, Taichung, Taiwan.
authors.forename: Shao-Keh
authors.initials: SK
authors.lastname: Hsu
authors.affiliation: Department of Sports Medicine, College of Health Care, China Medical University, Taichung, Taiwan.|Department of Orthopedic Surgery, China Medical University Beigang Hospital, Yunlin County, Taiwan.
authors.forename: Yi-Chin
authors.initials: YC
authors.lastname: Fong
authors.affiliation: 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.
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Tang
mesh_terms: D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002813:Chondrosarcoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D020738:Leptin / Q000378:metabolism*; D042583:Lymphangiogenesis; D035683:MicroRNAs / Q000096:biosynthesis*; D009363:Neoplasm Proteins / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000096:biosynthesis*; D042582:Vascular Endothelial Growth Factor C / Q000096:biosynthesis*
chemical_list: D020738:Leptin; C531388:MIRN27 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; C467486:VEGFC protein, human; D042582:Vascular Endothelial Growth Factor C