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Cell Death Dis. 2017 Aug 3;8(8):e2964. doi: 10.1038/cddis.2017.354.

Brain-derived neurotrophic factor promotes VEGF-C-dependent lymphangiogenesis by suppressing miR-624-3p in human chondrosarcoma cells.

Author information

1
Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
2
Department of Medicine, Mackay Medical College, New Taipei City, Taiwan.
3
Department of Fragrance and Cosmetic Science, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
4
Department of Orthopedic Surgery, Kaohsiung Chang Gung Memorial Hospital Medical Center, Kaohsiung, Taiwan.
5
Department of Orthopaedics, MacKay Memorial Hospital, Taipei, Taiwan.
6
Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli County, Taiwan.
7
Institute of Molecular Medicine, National Tsing-Hua University, Hsinchu, Taiwan.
8
Department of Sports Medicine, College of Health Care, China Medical University, Taichung, Taiwan.
9
Department of Orthopaedic Surgery, China Medical University Beigang Hospital, Yun-Lin County, Taiwan.
10
Department of Gastroenterology, Hsinchu MacKay Memorial Hospital, Hsinchu City, Taiwan.
11
Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan.
12
Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan.

Abstract

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.

PMID:
28771226
PMCID:
PMC5596545
DOI:
10.1038/cddis.2017.354
[Indexed for MEDLINE]
Free PMC Article

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