Osteoclastic miR-214 targets TRAF3 to contribute to osteolytic bone metastasis of breast cancer.
Osteoclastic miR-214 targets TRAF3 to contribute to osteolytic bone metastasis of breast cancer.
复制标题
破骨细胞 miR-214 靶向 TRAF3，促进乳腺癌的溶骨性骨转移。
DOI：
10.1038/srep40487
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发表时间：
2017-01-10
影响因子：
4.6
通讯作者：
Zhang G
中科院分区：
文献类型：
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作者：
Liu J;Li D;Dang L;Liang C;Guo B;Lu C;He X;Cheung HY;He B;Liu B;Li F;Lu J;Wang L;Shaikh AB;Jiang F;Lu C;Peng S;Zhang Z;Zhang BT;Pan X;Xiao L;Lu A;Zhang G
骨钙素miRNAs在乳腺癌溶骨性骨转移（OBM）中的调控作用尚不清楚。在这里，我们检查了人骨标本中破骨细胞生成miRNAs的表达谱，并确定miR-214- 3 p在OBM乳腺癌患者中显著上调。因此，我们发现在人乳腺癌异种移植裸鼠（BCX）OBM的发展过程中，破骨细胞内的miR-214- 3 p增加，这与骨吸收增加相关。此外，在裸鼠中基因切除骨细胞miR-214- 3 p可防止OBM的发展。来自MDA-MB-231细胞的条件培养基显著刺激miR-214- 3 p表达以促进破骨细胞分化。在机制上，一系列体外研究表明miR-214- 3 p直接靶向Traf 3以促进破骨细胞活性和骨吸收活性。此外，与同窝对照组相比，破骨细胞特异性miR-214- 3 p敲入小鼠的骨吸收显著增加，在用含Traf 3 3′ UTR的质粒进行破骨细胞靶向治疗后，骨吸收减弱。在BCX裸小鼠中，破骨细胞靶向的Eclomir-214- 3 p递送可分别恢复TRAF 3蛋白表达和减弱OBM的发展。总的来说，抑制骨细胞miR-214- 3 p可能是乳腺癌OBM患者的潜在治疗策略。同时，骨内TRAF 3可能是一个有前途的生物标志物，用于评估Escheromir-214- 3 p的治疗反应。
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.