PMID- 28771226 OWN - NLM STAT- MEDLINE DCOM- 20180417 LR - 20231112 IS - 2041-4889 (Electronic) VI - 8 IP - 8 DP - 2017 Aug 3 TI - Brain-derived neurotrophic factor promotes VEGF-C-dependent lymphangiogenesis by suppressing miR-624-3p in human chondrosarcoma cells. PG - e2964 LID - 10.1038/cddis.2017.354 [doi] AB - Chondrosarcoma is the second most common primary malignancy of bone, and one of the most difficult bone tumors to diagnose and treat. It is well known that increased levels of vascular endothelial growth factor-C (VEGF-C) promote active tumor lymphangiogenesis and lymphatic tumor spread to regional lymph nodes. Brain-derived neurotrophic factor (BDNF) is known to promote metastasis in human chondrosarcoma cells. Knowing more about the mechanism of BDNF in VEGF-C expression and lymphangiogenesis in human chondrosarcoma would improve our understanding as how to prevent chondrosarcoma angiogenesis and metastasis, which currently lacks effective adjuvant treatment. Here, we found that BDNF expression was at least 2.5-fold higher in the highly migratory JJ012(S10) cell line as compared with the primordial cell line (JJ012). In addition, VEGF-C expression and secretion was markedly increased in JJ012(S10) cells. Conditioned medium from JJ012(S10) cells significantly promoted migration and tube formation of human lymphatic endothelial cells (LECs), whereas knockdown of BDNF attenuated LEC migration and tube formation by suppressing VEGF-C production in JJ012(S10) cells. Mechanistic investigations indicated that BDNF facilitated VEGF-C-dependent lymphangiogenesis through the MEK/ERK/mTOR signaling pathway. We also showed that microRNA (miR)-624-3p expression was negatively regulated by BDNF via the MEK/ERK/mTOR cascade. Importantly, BDNF knockdown profoundly inhibited tumor-associated lymphangiogenesis in vivo. Further analyses identified that BDNF promoted tumor lymphangiogenesis by downregulating miR-624-3p in human chondrosarcoma tissues. In conclusion, this study is the first to reveal the mechanism underlying BDNF-induced lymphangiogenesis. We suggest that BDNF may serve as a promising therapeutic target for the restriction of VEGF-C-mediated tumor lymphangiogenesis and lymphatic metastasis. FAU - Lin, Chih-Yang AU - Lin CY AD - Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan. FAU - Wang, Shih-Wei AU - Wang SW AD - Department of Medicine, Mackay Medical College, New Taipei City, Taiwan. FAU - Chen, Yen-Ling AU - Chen YL AD - Department of Fragrance and Cosmetic Science, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan. FAU - Chou, Wen-Yi AU - Chou WY AD - Department of Orthopedic Surgery, Kaohsiung Chang Gung Memorial Hospital Medical Center, Kaohsiung, Taiwan. FAU - Lin, Ting-Yi AU - Lin TY AD - Department of Medicine, Mackay Medical College, New Taipei City, Taiwan. FAU - Chen, Wei-Cheng AU - Chen WC AD - Department of Orthopaedics, MacKay Memorial Hospital, Taipei, Taiwan. FAU - Yang, Chen-Yu AU - Yang CY AD - Department of Orthopaedics, MacKay Memorial Hospital, Taipei, Taiwan. FAU - Liu, Shih-Chia AU - Liu SC AD - Department of Orthopaedics, MacKay Memorial Hospital, Taipei, Taiwan. FAU - Hsieh, Chia-Chu AU - Hsieh CC AD - Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli County, Taiwan. AD - Institute of Molecular Medicine, National Tsing-Hua University, Hsinchu, Taiwan. FAU - Fong, Yi-Chin AU - Fong YC AD - Department of Sports Medicine, College of Health Care, China Medical University, Taichung, Taiwan. AD - Department of Orthopaedic Surgery, China Medical University Beigang Hospital, Yun-Lin County, Taiwan. FAU - Wang, Po-Chuan AU - Wang PC AD - Department of Gastroenterology, Hsinchu MacKay Memorial Hospital, Hsinchu City, Taiwan. FAU - Tang, Chih-Hsin AU - Tang CH AD - Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan. AD - Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan. AD - Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20170803 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (MIRN624 microRNA, human) RN - 0 (MicroRNAs) RN - 0 (Neoplasm Proteins) RN - 0 (RNA, Neoplasm) RN - 0 (VEGFC protein, human) RN - 0 (Vascular Endothelial Growth Factor C) SB - IM MH - Adult MH - Bone Neoplasms/genetics/*metabolism/pathology MH - Brain-Derived Neurotrophic Factor/*pharmacology MH - Cell Line, Tumor MH - Chondrosarcoma/genetics/*metabolism/pathology MH - Female MH - Humans MH - Lymphangiogenesis/*drug effects MH - Male MH - MicroRNAs/*biosynthesis/genetics MH - Middle Aged MH - Neoplasm Proteins/*biosynthesis/genetics MH - RNA, Neoplasm/*biosynthesis/genetics MH - Vascular Endothelial Growth Factor C/*biosynthesis PMC - PMC5596545 COIS- The authors declare no conflict of interest. EDAT- 2017/08/05 06:00 MHDA- 2018/04/18 06:00 PMCR- 2017/08/01 CRDT- 2017/08/04 06:00 PHST- 2017/03/15 00:00 [received] PHST- 2017/06/22 00:00 [revised] PHST- 2017/06/23 00:00 [accepted] PHST- 2017/08/04 06:00 [entrez] PHST- 2017/08/05 06:00 [pubmed] PHST- 2018/04/18 06:00 [medline] PHST- 2017/08/01 00:00 [pmc-release] AID - cddis2017354 [pii] AID - 10.1038/cddis.2017.354 [doi] PST - epublish SO - Cell Death Dis. 2017 Aug 3;8(8):e2964. doi: 10.1038/cddis.2017.354.