多梳蛋白RNF2通过EGR1调控结肠癌细胞的增殖和凋亡

RNF2, also known as Ring1B/Ring2, is a component of the polycomb repression complex 1 (PRC1), which can mediate the mono-ubiquitination of Histone H2A, thus epigenetically regulate gene expression. RNF2 is highly expressed in many tumors, suggests that it might have an oncogenic function, but the mechanism is unknown. When RNF2 was knocked down in colon cancer HCT116 cells, cell proliferation was inhibited and obvious apoptosis was induced. By using genome-wide microarray analysis and confirmative experiment, we showed that the tumor suppressor EGR1 was upregulated in RNF2 knockdown cells, both in mRNA level and protein level, and the inhibition of EGR1 can partly rescue the inhibited cell proliferation and increased apoptosis in RNF2 knockdown cells. These results indicated that RNF2 may play an oncogenic role in cancer cells through the inhibition on EGR1. Based on these prior data, we plan to study the mechanism how RNF2 regulate EGR1, we also want to analyze the expression pattern of RNF2 and EGR1 in clinical colon cancer tissues, and evaluate the possibility to use RNF2 single or together with EGR1 as a biomarker for diagnosis and prognosis of colon cancer. This study will help us to understand the mechanism how RNF2 work as an oncogene, will also be helpful to discover new biomarker for diagnosis and new target for therapy in colon cancer.

RNF2是PRC1复合体的重要成员，在多种肿瘤组织中高表达，是潜在的癌基因，但作用机制不清。我们发现在结肠癌细胞中下调RNF2的表达可明显抑制细胞增殖，并引发凋亡。为了探求其机制，我们在HCT116细胞中下调RNF2后，利用基因芯片技术获得了多个潜在的受RNF2调控的差异表达基因。经验证，我们发现RNF2下调细胞中的肿瘤抑制基因EGR1的表达明显上调，而同时下调RNF2和EGR1可有效挽救RNF2表达下调所引起的增殖抑制和凋亡，提示RNF2可能通过对EGR1的转录调控而发挥癌基因的功能。我们拟在此基础上深入研究RNF2调节EGR1的具体机制，并利用临床结肠癌标本检测RNF2与EGR1的表达相关性，探讨RNF2单独或与EGR1联合作为结肠癌诊断和预后标志物的可行性。这项研究将明确RNF2发挥癌基因作用的具体机制，也将有助于发现新的结肠癌诊断和治疗靶点。

RNF2是PRC1复合体的重要成员，在多种肿瘤组织中高表达，是潜在的癌基因，但作用机制不清。我们前期发现在结肠癌细胞中下调RNF2的表达可明显抑制细胞增殖，并引发凋亡。为了探求其机制，我们在HCT116细胞中下调RNF2后，利用基因芯片技术获得了多个潜在的受RNF2调控的差异表达基因。经验证，我们发现在RNF2下调的细胞中，肿瘤抑制基因EGR1的表达明显上调，而同时下调RNF2和EGR1可有效挽救RNF2表达下调所引起的增殖抑制和凋亡，提示RNF2可能通过对EGR1的转录调控而发挥癌基因的功能。本课题在此基础上系统地研究了RNF2调节EGR1的具体机制，在临床结肠癌标本中检测了RNF2的表达，并分析了其与患者临床病理特征之间的关系。发现RNF2在结肠癌中呈特异性高表达，且其表达与患者的临床病理特征密切相关，可作为结肠癌患者的预后判断指标。此外， RNF2可直接结合于EGR1的启动子区，并可通过对H2A泛素化水平的调节而抑制其表达。这项研究明确了RNF2在结肠癌中具有癌基因的作用，阐明了其发挥癌基因作用的具体机制，并认为其可作为结肠癌诊断和治疗的有效靶点。