TRIM24调控mRNA可变剪切促进三阴型乳腺癌远端转移的机制研究

项目名称： TRIM24调控mRNA可变剪切促进三阴型乳腺癌远端转移的机制研究

项目编号： No.81472636

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 刘兆良

作者单位： 哈尔滨医科大学

项目金额： 64万元

中文摘要： 乳腺癌是一种高度异质性的肿瘤，肿瘤的远端转移是患者死亡的主要原因。其中三阴型乳腺癌预后不佳，远端转移率较高。乳腺癌细胞发生远端转移时，大量转移相关基因的mRNA前体发生可变剪切切换，研究表明这一切换发生在转录组水平上。但是目前并不清楚可变剪切切换在三阴型乳腺癌远端转移过程中是如何被调控的。我们证实TRIM24可以与剪切体蛋白相结合，并可以调节乳腺癌细胞中转移相关基因的可变剪切。与此相对应，TRIM24过量表达的乳腺癌患者预后较差，在三阴型乳腺癌细胞中沉默TRIM24显著降低了细胞的集落形成和迁移能力。以往的研究证明TRIM24可以识别组蛋白修饰H3K4me0和H3K23ac。据此我们提出假说：乳腺癌患者中过量表达的TRIM24通过识别H3K4me0和H3K23ac，偶联剪切体蛋白与染色质，调控转移相关基因的mRNA可变剪切切换，促进肿瘤的转移。

中文关键词： TRIM24；可变剪切；远端转移；C21_乳腺肿瘤；组蛋白修饰

英文摘要： Breast cancer is a very hetergenous disease. The major cause of breast cancer death is metastasis. Triple negative breast cancer has poor prognosis and high metastasis rate. During metastasis，pre-mRNAs of many metastasis-related genes are alternatively spliced (AS) and previous studies have shown that this AS switch occurs at transcriptome level. However, it is still not clear how AS is regulated when triple negative breast cancer metastasizes. Our preliminary data demonstrates that TRIM24 interacts with multiple splicing factors and regulates AS of metastasis-realated genes in breast cancer cells. In agreement with this, TRIM24 is overpressed in breast cancer and its overexpression is associated with poor prognosis. Silencing TRIM24 in triple-negative breast cancer cells significantly decreased their capacity of migration and colony formation. Previous study has shown that TRIM24 is a chromatin reader recognizing H3K4me0 and H3K23ac. Therefore, we hypothesize that overexpressed TRIM24 in triple negative breast cancer cells regconizes H3K4me0 and H3K23ac, couples splicing factors with chromatin, regulates AS of metastasis-related genes, thus promotes cancer cell to metastasize.

英文关键词： TRIM24;alternative splicing(AS);metastasis;breast cancer;histone modifications