Profilin1调控突变型p53蛋白"核-浆/线粒体"移位影响胰腺癌恶性潜能的实验研究

To pancreatic cancer p53 gene mutations have been proved to top as high as 70%, which is closely related to its malignant potential. The nucleus-cytoplasm/mitochondria shift of mutant p53 protein is a key point to intervent its function and restore its cancer suppression. In our previous work we are dedicated to screen the conjugate molecule that could interact with mutant p53 protein and then can influence the malignancy of pancreatic cancer by high throughput comparative proteomics-mass spectrometric analysis and low throughput identification. The result showed that an important structure protein Profilin1 is directly related to mutant p53 protein structure and its translocation from nucleus to cytoplasm/mitochondria, which is likely to continue to affect mutant p53 protein function. So we will focus the further researches on: (1) Reveal the molecular mechanism of Profilin1 regulation on mutation p53 protein; (2) Clarify the cancer suppressive mechanism of Profilin1 influencing the intracelllular shift of mutant p53 protein which consequently causes malignant potential intervention to pancreatic cancer; (3) Analysis of the correlation between Profilin1 / mutation p53 functional complex and clinical features of pancreatic cancer in order to look for the diagnostic and treatment target and to provide the scientific basis for validating the intervention effectiveness.

胰腺癌中p53基因突变高达70%，与胰腺癌的恶性潜能密切相关。突变型p53蛋白"核-浆/线粒体"移位是干预突变型p53蛋白功能,恢复其抑癌作用的关键调节点。我们前期工作：通过蛋白相互作用的高通量比较蛋白质组学-质谱分析技术和低通量筛选鉴定能与突变型p53蛋白相互作用进而可以影响胰腺癌恶性潜能的共轭分子，证实细胞内一个重要的结构蛋白Profilin1与突变型p53蛋白的结构和"核-浆/线粒体"移位直接相关，并可能进一步影响其功能。因此，现拟开展以下研究：（1）阐明Pfn1调控突变型p53蛋白"核-浆/线粒体"移位的分子机制；（2）揭示Pfn1调控突变型p53蛋白对胰腺癌恶性潜能的影响；(3)分析Pfn1/突变型p53蛋白功能复合体与胰腺癌临床病理特征及预后的相关性，为寻找胰腺癌诊治靶点，验证干预有效性提供重要的临床科研依据。

胰腺癌中p53基因突变高达70%，与胰腺癌的恶性潜能密切相关。突变型p53蛋白“核-浆/线粒体”移位是干预突变型p53蛋白功能,恢复其抑癌作用的关键调节点。我们前期工作致力于通过蛋白相互作用的高通量比较蛋白质组学-质谱分析和低通量筛选鉴定能与突变型p53蛋白相互作用进而可以影响胰腺癌恶性潜能的共轭分子，证实细胞内一个重要的结构蛋白Profilin1与突变型p53蛋白的结构和“核-浆/线粒体”移位直接相关，并可能进一步影响其功能，故开展以下研究：（1）阐明Pfn1调控突变型p53蛋白“核-浆/线粒体”移位的分子机制；（2）揭示Pfn1调控突变型p53蛋白对胰腺癌恶性潜能的影响；(3)分析Pfn1/突变型p53蛋白功能复合体与胰腺癌临床病理特征及预后的相关性，为寻找胰腺癌诊治靶点，验证干预有效性提供重要的临床科研依据。