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Research Paper|Volume 11, Issue 21|pp 9767—9777

Resistin enhances angiogenesis in osteosarcoma via the MAPK signaling pathway

Hsiao-Chi Tsai1, Shih-Ping Cheng1,2,3, Chien-Kuo Han4, Yuan-Li Huang4, Shih-Wei Wang3,5, Jie-Jen Lee2,3, Cheng-Ta Lai6, Yi-Chin Fong7,8, Chih-Hsin Tang4,9,10
  • 1Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan
  • 2Department of Surgery, MacKay Memorial Hospital and Mackay Medical College, Taipei, Taiwan
  • 3Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
  • 4Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan
  • 5Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
  • 6Division of Colon and Rectal Surgery, Department of Surgery, MacKay Memorial Hospital, Taipei, Taiwan
  • 7Department of Sports Medicine, College of Health Care, China Medical University, Taichung, Taiwan
  • 8Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan
  • 9School of Medicine, China Medical University, Taichung, Taiwan
  • 10Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
* Equal contribution
Received: August 2, 2019Accepted: October 28, 2019Published: November 13, 2019
https://doi.org/10.18632/aging.102423

Copyright © 2019 Tsai et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Over the last two decades, there have been no significant changes in patient outcomes in relation to the treatment of osteosarcoma, an aggressive malignant neoplasm. It is known that vascular endothelial growth factor-A (VEGF-A) plays a crucial role in angiogenesis and in osteosarcoma. Moreover, VEGF-A expression correlates with clinical stages of osteosarcoma. The adipokine resistin exhibits proinflammatory, proangiogenic and metastatic properties, and evidence suggests that resistin may serve as a prognostic biomarker linking obesity and inflammation to cancer. However, whether resistin has a role in osteosarcoma angiogenesis is unclear. This investigation shows that resistin promotes VEGF-A expression in human osteosarcoma cells and activates the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 signaling pathways, while ERK, JNK, and p38 inhibitors or their small interfering RNAs (siRNAs) inhibit resistin-induced VEGF-A expression as well as endothelial progenitor cell (EPC) migration and tube formation. We also found that resistin upregulates VEGF-A expression by enhancing activation of the transcription factor nuclear factor-kappa B (NF-κB). Finally, resistin promotes angiogenesis in the chick chorioallantoic membrane (CAM) model. Resistin appears to be a promising target for human osteosarcoma.