Abstract
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.
Highlights
Osteolytic metastasis is the most common form of bone metastasis in patients with breast cancer[1]
We found that elevated miR-214-3p within osteoclast could target TRAF3 to promote osteoclastic bone resorption during the development osteolytic bone metastasis (OBM)
Our results suggest that therapeutic inhibition of miR-214-3p in osteoclasts may be a potential therapeutic strategy for OBM with dominant osteoclastic bone resorption
Summary
Osteolytic metastasis is the most common form of bone metastasis in patients with breast cancer[1]. The metastatic cancer cell could cause exaggerated osteoclast formation and excessive bone resorption, leading to osteolytic bone metastasis (OBM)[2,3]. There is still a lack of miRNAs directly identified from human bone specimens from breast cancer individuals to contribute to the pathophysiological regulation of OBM. We showed that miR-214-3p was significantly upregulated in bone specimens from breast cancer patients with OBM as well as in osteoclasts from nude mice with human breast cancer xenografts (BCX) during OBM development, which was accompanied by the elevated bone resorption. Loss of miR-214-3p gene within osteoclasts prevented the development of OBM in nude mice with BCX. We found that osteoclast-targeted antagomir-214-3p treatment could attenuate OBM in nude mice with BCX. Our data suggest that inhibition of osteoclastic miR-214-3p may be a potential therapeutic strategy for breast cancer with OBM
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