血清miRNAs作为乳腺癌新型诊断标志物及mir-1911-3p的分子机制研究

乳腺癌已成为危害全球女性健康的重要问题，故寻找有效分子标志物对早期诊治有重要意义。研究表明miRNAs在肿瘤组织及血液中异常表达，参与肿瘤发生发展和转移过程。在前期研究中，我们通过高通量测序筛选乳腺癌患者血清差异表达miRNAs，经验证发现4种miRNAs水平在患者血清中显著下调，那么该四种血清miRNAs能否作为乳腺癌的早期诊断标志物？进一步研究发现其中的mir-1911-3p水平随细胞恶性程度增高而降低，其过表达显著抑制乳腺癌细胞增殖、迁移和侵袭，并下调PRLR和上调SENP1，这是否提示其作用机制涉及PRL通路或蛋白质SUMO化修饰？故本项目拟首先构建4种血清miRNAs诊断模型，评估其对乳腺癌的诊断效率、敏感性及特异性；其次从临床水平、细胞水平、分子水平、动物水平等多层次探索miR-1911-3p调控乳腺癌侵袭转移的分子机制，以期为乳腺癌诊治提供新的分子标志物和治疗靶点。

Breast cancer has become an important public health all over the world, so it is crucial to find early effective molecular markers for diagnosis and treatment. Abnormal expression of miRNAs has been found in tumor tissue and peripheral blood, and current studies reveal that miRNAs participate in the process of tumor development and metastasis. In our previous study, we screened the differentially expressed serum miRNA between the breast cancer patients and the healthy controls by high throughput sequencing. RT-qPCR confirmed that four kinds of miRNA in the serum of patients with breast cancer were significantly down-regulated. These findings indicated that the four kinds of serum miRNA profiles may be used as early diagnostic markers and novel therapeutic targets for breast cancer. Further study showed that reduced expression of mir-1911-3p was correlated with the increase of cell malignancy. Furthermore, mir-1911-3p mimics significantly inhibited cell proliferation, migration and invasion, down-regulated the expression of PRLR and up-regulated the expression of SENP1. These results indicate that PRL/PRLR pathway or protein SUMO modification pathway may be involved in miR-1911-3p-mediated antitumor effects. Therefore, in this project, we will first construct the diagnostic models using four kinds of serum miRNA profiles, and evaluate the diagnostic efficiency, including sensitivity and specificity to breast cancer. Second, we will focus on the molecular mechanism of mir-1911-3p regulating invasion and metastasis in breast cancer at the cellular and molecular level and tissue level, so as to provide the new diagnostic markers and therapeutic targets for breast cancer.