小核仁RNA-snord36A基因扩增诱导三阴性乳腺癌转移和化疗耐药性的作用及分子机制研究

Triple negative breast cancer (TNBC) are characterized by the absence of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER-2) expression. The characteristics of TNBC are prone to recurrence, distant metastasis and poor prognosis. Identification of key driver genes and elucidating the mechanism would be of great value for TNBC diagnosis and treatment. Small nucleolar RNA (snoRNA) is a kind of non-coding RNA involved in the occurrence and development of various tumors, but its role in TNBC is still unclear. Recently, using TCGA copy number amplification data, we found that snord36A is upregulated in TNBC. Its expression level was positively correlated with lymph node metastasis and poor prognosis of TNBC. Furthermore, we demonstrated that snord36A promotes TNBC cell aggressive phenotype, resistant to apoptosis induced by cisplatin and paclitaxel, and angiogenesis. Then, protein chips and RNA immunoprecipitation assay revealed that snord36A interacted with CXCL16 and RBM38. In the current project, we aim to explore the biological roles and underlying mechanisms in which snord36A promotes TNBC metastasis and resistant to apoptosis induced by cisplatin and paclitaxel, which will provide new biomarkers and targets for the diagnosis and treatment for TNBC.

三阴性乳腺癌易早期复发、远处转移、预后差，尚无针对性的标准治疗方案，寻找其关键调控基因，阐明其功能和分子机制，对三阴性乳腺癌的诊治有重要意义。小核仁RNA是一类参与多种肿瘤发生发展的非编码RNA，但其在三阴性乳腺癌中的作用尚不明确。我们前期通过TCGA拷贝数扩增数据筛选到在乳腺癌中表达显著上调、且其表达水平与TNBC的淋巴结转移、不良预后正相关的小核仁RNA-snord36A。进一步发现：①snord36A可促进三阴性乳腺癌细胞恶性表型的形成；②snord36A能够与趋化因子CXCL16和P53相关蛋白RBM38结合，并正向调控二者的表达。本项目拟利用多种技术和方法深层次解析snord36A通过CXCL16、RBM38诱导三阴性乳腺癌转移和耐药性的分子机制；同时，结合临床数据和PDX模型，探讨snord36A抑制剂联合铂类及紫杉类药物在三阴性乳腺癌中的作用，为三阴性乳腺癌的诊治提供新思路。

我们前期通过TCGA拷贝数扩增数据筛选到在乳腺癌中表达显著上调、且其表达水平与三阴性乳腺癌的淋巴结转移、不良预后正相关的小核仁RNA-snord36A。进一步发现：①snord36A可促进三阴性乳腺癌细胞恶性表型的形成；②snord36A能够结合P53相关蛋白RBM38，并正向调控其表达。因此，我们提出科学假设，snord36A 通过结合并上调 RBM38 的表达，抑制P53蛋白的表达，导致肿瘤细胞 DNA 损伤修复能力的失调，肿瘤发生耐药和转移。本课题以上述假设为研究内容，发现小核仁RNA snord36A可能通过结合RBM38蛋白将其稳定在细胞核，阻止其进入细胞浆进入泛素化降解过程。利用FDA批准的“老药库”筛选针对snord36A 的“老药”并通过乳腺癌类器官研究该“老药”对三阴性乳腺癌的治疗效果。本课题可为三阴性乳腺癌的耐药机制拓宽新思路，也为三阴性乳腺癌的治疗提供新策略。