PTEN缺失导致Runx2激活的分子机理及其在前列腺肿瘤发生和转移中的作用

项目名称： PTEN缺失导致Runx2激活的分子机理及其在前列腺肿瘤发生和转移中的作用

项目编号： No.81472415

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： 刘平

作者单位： 南京师范大学

项目金额： 75万元

中文摘要： 前列腺癌（PCa）是常见的恶性肿瘤之一，但其发生及转移的分子机制仍不很清楚。研究表明，肿瘤抑制因子PTEN常在肿瘤中缺失或突变；Runt-related转录因子2（Runx2）与前列腺肿瘤发生及转移密切相关。我们分析临床样本发现，前列腺肿瘤中，PTEN缺失总伴随着Runx2的高表达，而且与肿瘤的发生和转移相关。预实验结果也显示：细胞中PTEN表达缺失能显著提高Runx2的转录活性；小鼠体内，仅PTEN缺失不能引发前列腺肿瘤，但PTEN缺失并Runx2高表达就能产生前列腺肿瘤并引起转移。这些结果提示：PTEN缺失不仅与Runx2高活性有关，而且PTEN缺失联合Runx2高表达与前列腺肿瘤的发生和转移密切关联。本课题在此基础上，以前列腺肿瘤细胞、基因工程小鼠为研究模型，探究PTEN缺失激活Runx2的分子机理及其在前列腺肿瘤发生及转移中的作用机制，为探寻有效的临床治疗方案和药物积累理论基础。

中文关键词： PTEN；Runx2；p300；前列腺肿瘤；肿瘤发生和转移

英文摘要： Prostate cancer (PCa) is the most commonly diagnosed malignancy and the second leading cause of cancer death in men, but the etiology of this disease is not fully understood. The tumor suppressor gene PTEN is frequently mutated, deleted or expressed at reduced levels in human PCa. Runt-related transcription factor 2 (Runx2) has been implicated in human metastatic PCa. However, whether it plays a causal role in prostate epithelial cell transformation and prostate oncogenesis remains elusive. Our previous studies show that Runx2 overexpression correlates with reduced expression of PTEN in a cohort of human PCa specimens. Our preliminary data show that PTEN knockdown upregulates Runx2 target gene expression, increases serine/threonine phosphorylation on Runx2, enhances Runx2's interaction with protein acetyltransferase p300, and induces an increase in the levels of RNA polymerase II phosphorylated at serine-2 in heptad repeats (Pol II-S2p) at Runx2 target gene loci. By generating Runx2 conditional transgenic mice, we demonstrate that prostate-specific overexpression of Runx2 alone induces prostate epithelial cell transformation and low-grade prostate intraepithelial neoplasia (PIN), but in combination of Pten heterozygous deletion, causes early-life high-grade PIN/low-grade PCa (early prostate cancer). The objectives of this application are to determine how mechanistically PTEN inactivation affects Runx2 occupancy on chromatin and enhances Runx2-mediated gene transactivation in PCa cells, and to establish the role of Runx2 overexpression and PTEN haploinsufficiency in PCa initiation and in development of advanced PCa. This knowledge will lay the foundation for development of new therapeutic strategies that will improve the clinical outcome of PCa patients, especially those with PTEN and Runx2 alterations.

英文关键词： PTEN;Runx2;p300;Proetate Cancer;Initiation and Metastasis of tumor