Research Papers:
CCL3 promotes angiogenesis by dysregulation of miR-374b/ VEGF-A axis in human osteosarcoma cells
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Abstract
Yuan-Ya Liao1,2,*, Hsiao-Chi Tsai3,*, Pei-Yu Chou4, Shih-Wei Wang5, Hsien-Te Chen6,7, Yu-Min Lin8,9, I-Ping Chiang10, Tzu-Ming Chang11, Shao-Keh Hsu11, Ming-Chih Chou1,2, Chih-Hsin Tang3,12,13, Yi-Chin Fong6,14
1Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
2Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan
3Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
4Department of Nursing, Hung Kuang University, Taichung, Taiwan
5Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
6Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan
7School of Chinese Medicine, China Medical University, Taichung, Taiwan
8Department of Medicine, Chung Shan Medical University, Taichung, Taiwan
9Department of Orthopaedics, Taichung Veterans General Hospital, Taichung, Taiwan
10Department of Pathology, China Medical University Hospital, Taichung, Taiwan
11Department of Orthopedic Surgery, Tungs' Taichung Metroharbor Hospital, Taichung, Taiwan
12Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan
13Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan
14Department of Sports Medicine, College of Health Care, China Medical University, Taichung, Taiwan
*These authors have contributed equally to this work
Correspondence to:
Yi-Chin Fong, e-mail: [email protected]
Chih-Hsin Tang, e-mail: [email protected]
Ming-Chih Chou, e-mail: [email protected]
Keywords: MAPK, miR-374b, VEGF-A, angiogenesis, osteosarcoma
Received: July 27, 2015 Accepted: December 05, 2015 Published: December 21, 2015
ABSTRACT
Osteosarcoma is the most frequent bone tumor, characterized by a high metastatic potential. However, the crosstalk between chemokine (C-C motif) ligand 3 (CCL3), which facilitates tumor progression and metastasis. Vascular endothelial growth factor-A (VEGF-A), an angiogenesis inducer and a highly specific mitogen for endothelial cells, has not been well explored in human osteosarcoma. Here we demonstrate the correlation of CCL3 and VEGF-A expressions, quantified by immunohistochemistry, with the tumor stage of human osteosarcoma tissues. Furthermore, CCL3 promotes VEGF-A expression in human osteosarcoma cells that subsequently induces human endothelial progenitor cell (EPC) migration and tube formation. Phosphorylation of JNK, ERK, and p38 was found after CCL3 stimulation. In addition, JNK, ERK, and p38 inhibitors also abolished CCL3-induced VEGF-A expression and angiogenesis. We noted that CCL3 reduces the expression of miR-374b and miR-374b mimic by reversing CCL3-promoted VEGF-A expression and angiogenesis in vitro and in vivo. This study shows that CCL3 promotes VEGF-A expression and angiogenesis in human osteosarcoma cells by down-regulating miR-374b expression via JNK, ERK, and p38 signaling pathways. Thus, CCL3 may be a new molecular therapeutic target in osteosarcoma angiogenesis and metastasis.
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