miR-383通过调节破骨细胞分化抑制乳腺癌骨转移的作用机制研究

Bone metastasis is a common and devastating consequence of breast cancer. The most popular treatment is a class of drugs that target osteoclast function. However, due to the side effects and other disadvantages, it is important to develop alternative antiresorptive strategies. MicroRNAs are small non-coding RNAs that pricipally function in the spatiotemporal regulation of protein translation in animal cells. Recent reports about osteoclastogenesis indicated that microRNAs might serve as important regulators in osteoclast differentiation and function. Based on our previous research data, miR-383 was supposed to inhibit osteoclast differentitation and function though c-fos, thus might serve as a potential way in the treatment of breast cancer bone metastasis. In our present research, we would firstly adopt the techniques of miRs mimics/inhibitor to testify the effects of miR-383 on osteoclastogenesis and bone resorption; after that luciferase assay and gene over-expression techniques would be performed to explore the potential mechanisms of miR-383 on osteoclast; finally, we would adopt breast cancer bone metastasis animal model, synthesize and inject pre-miR-383 through vena caudalis to evaluate the therapeutic efficacy in vivo. We aim to provide experimental basis for revealing miR-383's therapeutic effect, molecular mechanism and clinical application value.

乳腺癌远处转移最常见于骨，一旦发生预后极差，靶向抑制破骨细胞功能是目前防治乳腺癌骨转移的新方向，但由于药物副作用等缺陷，寻找新的替代治疗显得尤为迫切和必要。最近研究指出，miRNAs在破骨细胞中发挥重要的调控作用。我们前期研究结果表明，miR-383可通过c-fos负调控破骨细胞功能，提示其可用于防治乳腺癌诱导骨转移的新途径。本项目拟在此基础上，采用miRNAs沉默/过表达技术，明确miR-383对破骨细胞分化、功能的影响；其次，采用荧光素酶报告基因和挽救实验，探讨其靶基因和可能作用机制；最后在体内建立乳腺癌骨转移模型，利用miRNA沉默技术，尾静脉注射pre-miR-383，明确miR-383治疗乳腺癌诱导的骨转移的作用效果，进而为治疗乳腺癌骨转移提供一种新思路，也为miRNAs治疗该类疾病提供实验依据和方法借鉴。

乳腺癌远处转移最常见于骨，一旦发生预后极差，靶向抑制破骨细胞功能是目前防治乳腺 癌骨转移的新方向，但由于药物副作用等缺陷，寻找新的替代治疗显得尤为迫切和必要。最近研究指出，miRNAs在破骨细胞中发挥重要的调控作用，我们前期研究结果表明，miR-383可通过c-fos负调控破骨细胞功能，提示其可用于防治乳腺癌诱导骨转移的新途径。因此，我们通过miRNAs沉默/过表达技术，检测miR-383对乳腺癌诱导破骨分化、骨吸收和基因表达的影响；通过转染c-fos挽救实验，进一步验证miR-383与靶基因c-fos的调控关系；通过建立乳腺癌骨转移模型，尾静脉注射pre-miR-383明确miR-383治疗乳腺癌诱导的骨转移的作用效果；研究结果提示：miR-383在乳腺癌诱导的破骨细胞活化中显著下调，而c-fos表达显著上调，生物信息学分析提示其可能作用靶点为c-fos；miR-383沉默或过表达对破骨细胞分化和功能存在负调控作用，c-fos挽救实验验证miR-383通过调控破骨细胞功能靶点c-fos调控破骨细胞分化功能与基因表达；体内试验证实miR-383对乳腺癌骨转移具有骨保护作用。因此，miR383为治疗乳腺癌骨转移提供一种新思路，为miRNAs治疗该类疾病提供实验依据和方法借鉴。