CCL5 promotes VEGF-C production and induces lymphangiogenesis by suppressing miR-507 in human chondrosarcoma cells

// Li-Hong Wang 1, * , Chih-Yang Lin 2 , Shih-Chia Liu 3 , Guan-Ting Liu 2, * , Yen-Ling Chen 4 , Jih-Jung Chen 5 , Chia-Han Chan 3 , Ting-Yi Lin 6 , Chi-Kuan Chen 6, 7 , Guo-Hong Xu 1 , Shiou-Sheng Chen 8, 9 , Chih-Hsin Tang 2, 10, 11 , Shih-Wei Wang 6 1 Department of Orthopedics, Dongyang People's Hospital, Wenzhou Medical University, Dongyang, China 2 Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan 3 Department of Orthopaedics, Mackay Memorial Hospital, Taipei, Taiwan 4 Department of Fragrance and Cosmetic Science, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan 5 Department of Pharmacy, Tajen University, Pingtung, Taiwan 6 Department of Medicine, Mackay Medical College, New Taipei City, Taiwan 7 Department of Pathology, Mackay Memorial Hospital, Taipei, Taiwan 8 Department of Urology, National Yang-Ming University School of Medicine, Taipei, Taiwan 9 Division of Urology, Taipei City Hospital Renai Branch, Taipei, Taiwan 10 Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan 11 Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan * These authors have contributed equally to this work Correspondence to: Chih-Hsin Tang, e-mail: chtang@mail.cmu.edu.tw Shih-Wei Wang, e-mail: shihwei@mmc.edu.tw Keywords: CCL5, VEGF-C, lymphangiogenesis, miR-507 Received: November 24, 2015      Accepted: April 24, 2016      Published: May 6, 2016 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 major lymphangiogenic factor, and makes crucial contributions to tumor lymphangiogenesis and lymphatic metastasis. Chemokine CCL5 has been reported to facilitate angiogenesis and metastasis in chondrosarcoma. However, the effect of chemokine CCL5 on VEGF-C regulation and lymphangiogenesis in chondrosarcoma has largely remained a mystery. In this study, we showed a clinical correlation between CCL5 and VEGF-C as well as tumor stage in human chondrosarcoma tissues. We further demonstrated that CCL5 promoted VEGF-C expression and secretion in human chondrosarcoma cells. The conditioned medium (CM) from CCL5-overexpressed cells significantly induced tube formation of human lymphatic endothelial cells (LECs). Mechanistic investigations showed that CCL5 activated VEGF-C-dependent lymphangiogenesis by down-regulating miR-507. Moreover, inhibiting CCL5 dramatically reduced VEGF-C and lymphangiogenesis in the chondrosarcoma xenograft animal model. Collectively, we document for the first time that CCL5 induces tumor lymphangiogenesis by the induction of VEGF-C in human cancer cells. Our present study reveals miR-507/VEGF-C signaling as a novel mechanism in CCL5-mediated tumor lymphangiogenesis. Targeting both CCL5 and VEGF-C pathways might serve as the potential therapeutic strategy to block cancer progression and metastasis in chondrosarcoma.