已报道酪氨酸磷酸酶SHP2在多种肿瘤中为癌基因，但我们发现SHP2在结直肠癌中可能为肿瘤抑制基因。尽管SHP2在肝癌中的肿瘤抑制机制已被报道，但其在结直肠癌和肝癌中的细胞定位不同，提示其机制存在组织、器官特异性。本研究拟在前期工作基础上围绕结直肠癌SHP2展开如下研究：①用噬菌体展示肽和免疫沉淀等方法，确定对胞核SHP2有紧密调节作用的蛋白；②用基因芯片和Western blotting等方法，揭示SHP2及其关键调节蛋白在细胞DNA损伤后参与有丝分裂灾难形成的信号通路，并用组织芯片技术评价这些信号蛋白对患者预后预测的价值；③基于肿瘤细胞及其小鼠接种模型，评价SHP2、其调节蛋白、顺铂、PARP抑制剂等单独或组合使用对结直肠癌肿瘤的体外、体内抑制作用。本课题完成后，不仅能明确SHP2在结直肠癌进展中的生物功能和分子机制，而且为结直肠癌的预后预测和个体化治疗提供新思路。

It has been reported that SHP2 plays an oncogenic role in leukemia and several types of solid tumors. However, we recently found that SHP2 might serve as a tumor suppressor in colorectal cancer (CRC). Although SHP2 has been reported to be a tumor suppressor in liver cancer, its subcelluar localizations are different in CRC and liver cancer, suggesting there may be contex-dependent molecular mechanisms in these two types of cancers. In this proposal, we first plan to identify the protein partners that closely regulate nuclear SHP2 using phage display peptide library screening and Immunoprecipitation. Then, we will elucidate the mechanisms underlying the role of SHP2 and its key protein partners in the regulation of the development of mitotic catastrophe using relevant analysis methods including siRNA silencing, mRNA profiling microarry and Western blotting, and then construct an immunohistochemical signature using downstream genes of SHP2 and/or its protein partners to predict the prognosis of patients with CRC. Finally, we will evaluate the tumor suppression function of SHP2, its protein partners, Cisplatin, and PARP inhibitors, using alone or in combination, with CRC cell lines and mouse models. Our proposed studies will establish a new mechanistic framework for understanding the biological functions and molecular mechanisms of SHP2 in CRC progression and provide prognosis biomarkers and new therapeutic targets of CRC.