Osteoclastic miR-214 targets TRAF3 to contribute to osteolytic bone metastasis of breast cancer

Jin LIU, Defang LI, Lei Dang, Chao LIANG, Baosheng GUO, Cheng Lu, Xiaojuan He, Hilda Y.S. Cheung, Bing He, Biao Liu, Fangfei LI, Jun Lu, Luyao Wang, Atik Badshah Shaikh, Feng Jiang, Changwei Lu, Songlin Peng, Zongkang Zhang, Bao Ting Zhang, Xiaohua PanLianbo Xiao, Aiping LYU, Ge ZHANG*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

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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.

Original languageEnglish
Article number40487
Number of pages13
JournalScientific Reports
Publication statusPublished - 10 Jan 2017

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