DJ-1及其氧化还原修饰参与结直肠癌发生发展的机制与临床意义研究

结直肠癌是临床上常见的恶性肿瘤，严重危害人类身体健康。DJ-1是我们前期在活性氧促进结直肠癌转移研究中筛选到的标志物之一，结果发表于Mol Cell Proteomics杂志。该蛋白在抵御氧化应激和细胞死亡、以及调控Akt等多个关键通路方面均具有重要作用，但其在结直肠癌发生发展中的作用与机制仍不清楚。我们后续研究发现：DJ-1在结直肠癌中高表达，且与肿瘤浸润深度及分期分级等密切关联；干扰其表达可显著抑制结直肠癌细胞增殖和迁移能力；其氧化还原修饰与结直肠癌细胞的转移潜能相关；蛋白质相互作用分析结果也提示其可激活Akt等通路。本项目拟在此基础上，综合采用多种分子肿瘤学研究技术，深入研究 DJ-1异常表达以及ROS介导的氧化还原修饰在结直肠癌发生发展中的生物学功能，阐明DJ-1及其氧化还原修饰在结直肠癌发生发展中的作用机制与临床意义，探讨其作为结直肠癌早期诊断标志物或药物靶标的潜在应用价值。

Colorectal cancer (CRC) is a common malignancy which causes global health burden. In our previous proteomics study, we identified DJ-1 as a redox-sensitive protein that harbors the potential to be candidate biomarker in reactive oxygen species (ROS)-induced migration and invasion in CRC cells (Lei et al. Molecular & Cellular Proteomics 2011). DJ-1 is involved in the regulation of cellular redox signaling cascades such as Akt signaling, and plays crucial roles in the defense against oxidative stress and cell death. However, the role that DJ-1 playing in the development and progression of CRC as well as the mechanisms regarding redox modification of DJ-1 remains unknown. Our further functional analysis revealed that: 1) the expression of DJ-1 was markedly up-regulated in tumor tissues compared with normal control, and was significantly correlated with the invasion depth, TNM stage and histo-differentiation; 2) the suppression of DJ-1 expression reduced the proliferative and migratory capacity of CRC cells; 3) the redox modification of DJ-1 was associated with metastatic potential of CRC; 4) interaction proteomics analysis implied the involvement of multiple potential DJ-1-binding proteins in various signaling pathways such as PI3K-Akt signaling. These results suggest that the expression and redox modification of DJ-1 play an important role in the development and progression of CRC. In this project, we will apply the molecular and cell biology strategies combined with animal models to comprehensively interrogate the biological functions of DJ-1 and clarify the role of its redox modification in the proliferation and metastasis of CRC cells. Further, we will use larger selected clinical cohorts to analyze the clinical and pathological significance of DJ-1. Our study aims to evaluate the potential of DJ-1 as an early diagnostic biomarker or drug target in CRC, which will pave the road for translational medicine.