microRNA-124 inhibits bone metastasis of breast cancer by repressing Interleukin-11.
microRNA-124 inhibits bone metastasis of breast cancer by repressing Interleukin-11.
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microRNA-124通过抑制Interleukin-11抑制乳腺癌骨转移
DOI：
10.1186/s12943-017-0746-0
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发表时间：
2018-01-17
期刊：
影响因子：
37.3
通讯作者：
Xiao JR
中科院分区：
文献类型：
--
作者：
Cai WL;Huang WD;Li B;Chen TR;Li ZX;Zhao CL;Li HY;Wu YM;Yan WJ;Xiao JR
研究背景大多数晚期乳腺癌患者都有骨转移，导致骨折和神经卡压综合征。在乳腺癌向骨转移的过程中，microRNA表达异常是一个重要事件。MicroRNA-124(miR-124)已被证明具有抑制肿瘤进展的作用，但其对乳腺癌骨转移的作用尚未见报道。因此，本研究旨在探讨miR-124在乳腺癌骨转移中的作用及其机制。方法采用原位杂交技术检测miR-124在乳腺癌组织和骨转移组织中的表达。建立脑室注射模型，探讨miR-124对体内骨转移的影响。体外实验验证了癌细胞来源的miR-124在破骨细胞前体细胞分化中的作用。采用双荧光素酶报告实验确定IL-11为miR-124靶点。通过Kaplan-Meier分析确定miR-124/IL-11在乳腺癌骨转移患者预后中的作用。MiR-124表达下调与侵袭性临床特征和较短的骨转移无生存期和总生存期相关。在体内，miR-124的修复受到抑制，而miR-124的抑制促进了乳腺癌细胞的骨转移。在细胞水平上，功能获得和功能丧失分析表明，癌细胞来源的miR-124抑制破骨细胞前体细胞的存活和分化。在分子水平上，我们通过体外和体内实验证明了IL-11部分介导了miR-124抑制破骨细胞的生成。此外，IL-11水平与miR-124水平呈负相关，IL-11在骨转移中表达上调与预后不良相关。结论发现异常表达的miR-124/IL-11轴有助于阐明乳腺癌骨转移的机制，发现新的预后标志物，并有助于开发新的治疗靶点来治疗甚至预防乳腺癌的骨转移。
BackgroundMost patients with breast cancer in advanced stages of the disease suffer from bone metastases which lead to fractures and nerve compression syndromes. microRNA dysregulation is an important event in the metastases of breast cancer to bone. microRNA-124 (miR-124) has been proved to inhibit cancer progression, whereas its effect on bone metastases of breast cancer has not been reported. Therefore, this study aimed to investigate the role and underlying mechanism of miR-124 in bone metastases of breast cancer.MethodsIn situ hybridization (ISH) was used to detect the expression of miR-124 in breast cancer tissues and bone metastatic tissues. Ventricle injection model was constructed to explore the effect of miR-124 on bone metastasis in vivo. The function of cancer cell derived miR-124 in the differentiation of osteoclast progenitor cells was verified in vitro. Dual-luciferase reporter assay was conducted to confirm Interleukin-11 (IL-11) as a miR-124 target. The involvement of miR-124/IL-11 in the prognosis of breast cancer patients with bone metastasis was determined by Kaplan-Meier analysis.ResultsHerein, we found that miR-124 was significantly reduced in metastatic bone tissues from breast cancers. Down-regulation of miR-124 was associated with aggressive clinical characteristics and shorter bone metastasis-free survival and overall survival. Restoration of miR-124 suppressed, while inhibition of miR-124 promoted the bone metastasis of breast cancer cells in vivo. At the cellular level, gain of function and loss-of function assays indicated that cancer cell-derived miR-124 inhibited the survival and differentiation of osteoclast progenitor cells. At the molecular level, we demonstrated that IL-11 partially mediated osteoclastogenesis suppression by miR-124 using in vitro and in vivo assays. Furthermore, IL-11 levels were inversely correlated with miR-124, and up-regulation IL-11 in bone metastases was associated with a poor prognosis.ConclusionsThus, the identification of a dysregulated miR-124/IL-11 axis helps elucidate mechanisms of breast cancer metastases to bone, uncovers new prognostic markers, and facilitates the development of novel therapeutic targets to treat and even prevent bone metastases of breast cancer.
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对于乳腺癌患者而言，microRNA-124的表达降低是独立的不利预后因素。
影响因子：
2.6
作者：
Dong LL;Chen LM;Wang WM;Zhang LM
通讯作者：
Zhang LM
影响因子：
4.1
作者：
Hollensen, Anne Kruse;Bak, Rasmus O.;Mikkelsen, Jacob Giehm
通讯作者：
Mikkelsen, Jacob Giehm
影响因子：
3.7
作者：
Hanavadi, Satheesha;Martin, Tracey A.;Jiang, Wen G.
通讯作者：
Jiang, Wen G.
影响因子：
37.3
作者：
Li L;Luo J;Wang B;Wang D;Xie X;Yuan L;Guo J;Xi S;Gao J;Lin X;Kong Y;Xu X;Tang H;Xie X;Liu M
通讯作者：
Liu M
影响因子：
3.7
作者：
Joung YH;Darvin P;Kang DY;Sp N;Byun HJ;Lee CH;Lee HK;Yang YM
通讯作者：
Yang YM