title: CCL5 promotes VEGF-C production and induces lymphangiogenesis by suppressing miR-507 in human chondrosarcoma cells.
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.
authors.affiliation: Department of Orthopedics, Dongyang People's Hospital, Wenzhou Medical University, Dongyang, China.
authors.forename: Li-Hong
authors.initials: LH
authors.lastname: Wang
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Chih-Yang
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Department of Orthopaedics, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Shih-Chia
authors.initials: SC
authors.lastname: Liu
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Guan-Ting
authors.initials: GT
authors.lastname: Liu
authors.affiliation: Department of Fragrance and Cosmetic Science, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yen-Ling
authors.initials: YL
authors.lastname: Chen
authors.affiliation: Department of Pharmacy, Tajen University, Pingtung, Taiwan.
authors.forename: Jih-Jung
authors.initials: JJ
authors.lastname: Chen
authors.affiliation: Department of Orthopaedics, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Chia-Han
authors.initials: CH
authors.lastname: Chan
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei City, Taiwan.
authors.forename: Ting-Yi
authors.initials: TY
authors.lastname: Lin
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei City, Taiwan.|Department of Pathology, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Chi-Kuan
authors.initials: CK
authors.lastname: Chen
authors.affiliation: Department of Orthopedics, Dongyang People's Hospital, Wenzhou Medical University, Dongyang, China.
authors.forename: Guo-Hong
authors.initials: GH
authors.lastname: Xu
authors.affiliation: Department of Urology, National Yang-Ming University School of Medicine, Taipei, Taiwan.|Division of Urology, Taipei City Hospital Renai Branch, Taipei, Taiwan.
authors.forename: Shiou-Sheng
authors.initials: SS
authors.lastname: Chen
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.|Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan.|Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan.
authors.forename: Chih-Hsin
authors.initials: CH
authors.lastname: Tang
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei City, Taiwan.
authors.forename: Shih-Wei
authors.initials: SW
authors.lastname: Wang
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D018946:Chemokine CCL5 / Q000378:metabolism*; D002813:Chondrosarcoma / Q000378:metabolism / Q000473:pathology*; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D064593:Heterografts; D006801:Humans; D042583:Lymphangiogenesis / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism*; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*
chemical_list: C483024:CCL5 protein, human; D018946:Chemokine CCL5; D035683:MicroRNAs; D042582:Vascular Endothelial Growth Factor C
keywords: CCL5; VEGF-C; lymphangiogenesis; miR-507