title: Adiponectin promotes VEGF-C-dependent lymphangiogenesis by inhibiting miR-27b through a CaMKII/AMPK/p38 signaling pathway in human chondrosarcoma cells.
abstract: Chondrosarcoma is the second most frequently occurring type of bone malignancy characterized by distant metastatic propensity. Vascular endothelial growth factor-C (VEGF-C) is the major lymphangiogenic factor, and makes crucial contributions to tumour lymphangiogenesis and lymphatic metastasis. Adiponectin is a protein hormone secreted predominantly by differentiated adipocytes. In recent years, adiponectin has also been indicated as facilitating tumorigenesis, angiogenesis and metastasis. However, the effect of adiponectin on VEGF-C regulation and lymphangiogenesis in chondrosarcoma has remained largely a mystery. In the present study, we have shown a clinical correlation between adiponectin and VEGF-C, as well as tumour stage, in human chondrosarcoma tissues. We further demonstrated that adiponectin promoted VEGF-C expression and secretion in human chondrosarcoma cells. The conditioned medium from adiponectin-treated cells significantly induced tube formation and migration of human lymphatic endothelial cells. In addition, adiponectin knock down inhibited lymphangiogenesis in vitro and in vivo We also found that adiponectin-induced VEGF-C is mediated by the calmodulin-dependent protein kinase II (CaMKII), AMP-activated protein kinase (AMPK) and p38 signaling pathway. Furthermore, the expression of miR-27b was negatively regulated by adiponectin via the CaMKII, AMPK and p38 cascade. The present study is the first to describe the mechanism of adiponectin-promoted lymphangiogenesis by up-regulating VEGF-C expression in chondrosarcomas. Thus, adiponectin could serve as a therapeutic target in chondrosarcoma metastasis and lymphangiogenesis.
authors.affiliation: Department of Orthopaedic Surgery, China Medical University Beigang Hospital, Yunlin County, Taiwan School of Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Chun-Yin
authors.initials: CY
authors.lastname: Huang
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 Orthopaedic Surgery, China Medical University Hospital, Taichung, Taiwan School of Chinese Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Hsien-Te
authors.initials: HT
authors.lastname: Chen
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 Orthopaedic Surgery, China Medical University Beigang Hospital, Yunlin County, Taiwan.
authors.forename: Yuan-Shun
authors.initials: YS
authors.lastname: Lo
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan School of Medicine, China Medical University, Taichung, Taiwan Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan chtang@mail.cmu.edu.tw.
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Tang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D052242:Adiponectin / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002813:Chondrosarcoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D042583:Lymphangiogenesis; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D052242:Adiponectin; C531388:MIRN27 microRNA, human; D035683:MicroRNAs; D042582:Vascular Endothelial Growth Factor C; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases
keywords: VEGF-C; adiponectin; chondrosarcoma; lymphangiogenesis; miR-27b