POH1靶向p53和Bim调控食管癌细胞凋亡的机制研究

Esophageal cancer (EC) is one of the most prevalent malignancies with high regional incidence and mortality in China. It has been demonstrated that deubiquitinating enzymes (DUBs) play important roles in cancer progression. Recently, we observed that POH1 expression was increased in EC cells, and connected with poor prognosis. Further study showed that POH1 silence inhibited cell proliferation and induced cell apoptosis. In addition, the knockdown of POH1 increased the expression of p53 and Bim via enhancing protein stability. Based on our findings, we assume that POH1 is involved in cell apoptosis by targeting p53 and Bim. In this study, we aim to determine the expression of POH1 in esophageal cancer and its clinical significance, to examine the role of POH1 in cell apoptosis, and to disclose the mechanism via which POH1 regulates p53 and Bim, using a series of biological and immunological experiments in cell and animal models. Our study is likely to provide not only a scientific basis for understanding the molecular mechanism of esophageal carcinogenesis, but also a promising therapeutic target.

食管癌是我国区域性高发且预后差的恶性肿瘤，泛素-蛋白酶体在肿瘤发生发展中发挥重要作用，但其在食管癌中的作用机制尚未明了。我们前期观察到泛素解离酶POH1在食管癌组织中高表达，与患者预后差相关；体外实验结果显示沉默POH1能抑制食管癌细胞增殖，激活线粒体途径诱导细胞凋亡；进一步研究发现，沉默POH1可增加p53和Bim的蛋白稳定性而上调其表达。因此，我们提出POH1靶向p53和Bim，参与食管癌细胞凋亡的假说。本项目拟利用大样本人体组织标本，多种细胞和动物模型，在蛋白表达及细胞功能上，明确POH1在食管癌中的表达及其意义，阐述POH1调控p53和Bim的分子机制及其在细胞凋亡中的作用，探讨靶向POH1干预食管癌的潜在作用，为诠释食管癌发生发展的分子机制和寻找治疗新靶点提供科学依据。

食管癌（EC)是我国一种预后差的恶性肿瘤，泛素-蛋白酶体在肿瘤发生发展中发挥重要作用，但其在食管癌的机制尚不清楚。在本项目的研究中，我们发现泛素解离酶POH1蛋白在EC细胞株和组织中的表达明显升高，且高表达与EC患者的生存率下降密切相关。体外实验表明，敲降POH1能够抑制EC细胞增殖，激活线粒体途径促进细胞凋亡；体内实验表明，干扰POH1表达显著降低EC细胞的生长，同时诱导EC细胞的凋亡。进一步研究发现，干扰p53或者Bim表达明显削减POH1衰减引起的EC细胞凋亡，POH1衰减可通过提升p53和Bim蛋白的稳定性，抑制它们泛素化过程，从而诱导EC细胞凋亡。总之，POH1可以通过降低p53和Bim蛋白的稳定性，促进它们的泛素化降解，进而抑制EC细胞凋亡。因此，本研究结果表明POH1是EC潜在的预后生物标记物和肿瘤治疗的靶点。