Adiponectin promotes VEGF-A-dependent angiogenesis in human chondrosarcoma through PI3K, Akt, mTOR, and HIF-α pathway
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Hsiang-Ping Lee1,2,*, Chih-Yang Lin3,*, Jhao-Sheng Shih3, Yi-Chin Fong4,5, Shih-Wei Wang6, Te-Mao Li7, Chih-Hsin Tang3,8,9
1Graduate Institute of Chinese Medicine, China Medical University, Taichung, Taiwan
2Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan
3Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
4Department of Sports Medicine, China Medical University, Taichung, Taiwan
5Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan
6Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
7School of Chinese Medicine, China Medical University, Taichung, Taiwan
8Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan
9Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan
*These authors have contributed equally to this work
Chih-Hsin Tang, e-mail: firstname.lastname@example.org
Te-Mao Li, e-mail: email@example.com
Keywords: adiponectin, chondrosarcoma, angiogenesis, VEGF-A, HIF
Received: May 05, 2015 Accepted: October 02, 2015 Published: October 12, 2015
Chondrosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and cause distant metastasis. Adiponectin is a protein hormone secreted predominantly by differentiated adipocytes. On the other hand, angiogenesis is a critical step in tumor growth and metastasis. However, the relationship of adiponectin with vascular endothelial growth factor-A (VEGF-A) expression and angiogenesis in human chondrosarcoma is mostly unknown. In this study we first demonstrated that the expression of adiponectin was correlated with tumor stage of human chondrosarcoma tissues. In addition, we also found that adiponectin increased VEGF-A expression in human chondrosarcoma cells and subsequently induced migration and tube formation in human endothelial progenitor cells (EPCs). Adiponectin promoted VEGF-A expression through adiponectin receptor (AdipoR), phosphoinositide 3 kinase (PI3K), Akt, mammalian target of rapamycin (mTOR), and hypoxia-inducible factor-1α (HIF)-1α signaling cascades. Knockdown of adiponectin decreased VEGF-A expression and also abolished chondrosarcoma conditional medium-mediated tube formation in EPCs in vitro as well as angiogenesis effects in the chick chorioallantoic membrane and Matrigel plug nude mice model in vivo. Therefore, adiponectin is crucial for tumor angiogenesis and growth, which may represent a novel target for anti-angiogenic therapy in human chondrosarcoma.
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