Journal
SCIENTIFIC REPORTS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/srep40487
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Funding
- Ministry of Science and Technology of China [2013ZX09301307]
- Hong Kong General Research Fund [HKBU479111, HKBU478312, HKBU262913, HKBU261113, CUHK14112915, CUHK489213]
- Natural Science Foundation Council of China [81602556, 81272045, 81401833, 81470072, N_HKBU435/12]
- Research Grants Council of China [N_HKBU435/12]
- Croucher Foundation [CAS14BU/CAS14201]
- Interdisciplinary Research Matching Scheme (IRMS) of Hong Kong Baptist University [RC-IRMS/12-13/02, RC-IRMS/13-14/02]
- Hong Kong Baptist University Strategic Development Fund (SDF) [SDF13-1209-P01]
- Hong Kong Research Grants Council (RGC) Early Career Scheme (ECS) [489213]
- Inter-institutional Collaborative Research Scheme of Hong Kong Baptist University [RC-ICRS/14-15/01]
- Faculty Research Grant of Hong Kong Baptist University [FRG1/13-14/024, FRG2/12-13/027, FRG2/14-15/010]
- China Academy of Chinese Medical Sciences [Z0252, Z0293]
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The role of osteoclastic miRNAs in regulating osteolytic bone metastasis (OBM) of breast cancer is still underexplored. Here, we examined the expression profiles of osteoclastogenic miRNAs in human bone specimens and identified that miR-214-3p was significantly upregulated in breast cancer patients with OBM. Consistently, we found increased miR-214-3p within osteoclasts, which was associated with the elevated bone resorption, during the development of OBM in human breast cancer xenografted nude mice (BCX). Furthermore, genetic ablation of osteoclastic miR-214-3p in nude mice prevent the development of OBM. Conditioned medium from MDA-MB-231 cells dramatically stimulated miR-214-3p expression to promote osteoclast differentiation. Mechanistically, a series of in vitro study showed that miR-214-3p directly targeted Traf3 to promote osteoclast activity and bone-resorbing activity. In addition, osteoclast-specific miR-214-3p knock-in mice showed remarkably increased bone resorption when compared to the littermate controls, which was attenuated after osteoclast-targeted treatment with Traf3 3'UTR-containing plasmid. In BCX nude mice, osteoclast-targeted antagomir-214-3p delivery could recover the TRAF3 protein expression and attenuate the development of OBM, respectively. Collectively, inhibition of osteoclastic miR-214-3p may be a potential therapeutic strategy for breast cancer patients with OBM. Meanwhile, the intraosseous TRAF3 could be a promising biomarker for evaluation of the treatment response of antagomir-214-3p.
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