circBCBM1靶向结合miR-145调控乳腺癌脑转移的机制研究

Metastatic brain tumors represent the most common cerebral neoplasm in adults and breast cancer is the second most common solid malignancy that metastasizes to the brain. Despite this clinical importance, the molecular basis of breast cancer brain metastasis (BCBM) is poorly understood. We here focus on the regulation of circular RNA in BCBM. In our previous study, we identified a novel circular RNA, named circBCBM1, with a higher expression in the brain-tropic clones versus lung-tropic and bone-tropic clones of breast cancer. This circular RNA could act as a sponge of miR-145, resulting in promoting the proliferation and migration of BCBM cells. In this study, we will first confirm the effects of circBCBM1 on BCBM in vitro and in vivo, and then investigate the underlying mechanisms and regulating axis of circBCBM1 via miR-145 and its target CDH2. Subsequently, we will test the association of the expression levels of circBCBM1, miR-145 and CDH2 with BCBM and evaluate the significance of these molecules in the prognosis of breast cancer. We believe that our work will clarify the molecular mechanisms and regulating axis of BCBM and may provide evidence for the novel applications of these molecules in BCBM.

乳腺癌是引发脑转移的第二位实体恶性肿瘤，其确切的分子机制尚不明确。本项目拟从表观遗传学角度立足环状RNA调控轴阐释乳腺癌脑转移的新机制。申请者前期筛选获得乳腺癌脑转移细胞高表达的环状RNA circBCBM1，该分子可以与miR-145结合，促进肿瘤细胞增殖及迁移。在此基础上本项目拟通过体内外实验进一步验证circBCBM1的功能；解析其靶向结合miR-145调控乳腺癌脑转移的机制：探索circBCBM1上调表达机制，确认其与miR-145互作关系，验证CDH2是否为miR-145调控的下游靶分子，阐明circBCBM1/miR-145/CDH2作用轴在乳腺癌脑转移中的调控模式；回顾性分析circBCBM1、miR-145及CDH2与乳腺癌脑转移的临床相关性及预后判断价值。本项目研究结果将进一步阐明乳腺癌脑转移的分子机制及调控网络，并为相关靶点应用于临床转化医学奠定理论基础。

乳腺癌是引发脑转移的第二位实体恶性肿瘤，其确切的分子机制尚不明确。本项目从表观遗传学角度立足环状RNA调控轴阐释乳腺癌脑转移的新机制。本项目研究结果表明circBCBM1在乳腺癌脑转移细胞中高表达；功能学实验结果表明circBCBM1在体外细胞水平促进肿瘤细胞增殖及迁移，在体内动物模型中促进肿瘤生长及脑转移；机制上，circBCBM1作为miR-125a sponge抑制其活性，可解除miR-125a对下游靶基因BRD4的抑制，上调BRD4的表达水平。BRD4通过SHH信号通路上调MMP9的表达，促进肿瘤细胞迁移，破坏血脑屏障，进而促进乳腺癌脑转移。circBCBM1在乳腺癌脑转移组织和血浆标本中高表达，且乳腺癌原发灶中circBCBM1的高表达与患者无脑转移生存期（BMFS）较短相关。以上结果说明circBCBM1通过circBCBM1/miR-125a/BRD4调控乳腺癌脑转移，circBCBM1可作为乳腺癌脑转移潜在的诊断或预后标志物，亦可用作潜在的乳腺癌脑转移治疗靶标。因此，本项目的研究结果进一步阐明了乳腺癌脑转移的分子机制及调控网络，并为相关靶点应用于临床转化医学奠定了理论基础。