EZH2通过表观抑制E-cadherin促进肾癌进展的分子机制及其预测患者术后生存的临床意义研究

发布时间：2018-11-20 19:10

【摘要】：第一部分前瞻性研究肾细胞癌EZH2的表达水平及其活性对预后的预测目的：已有报道EZH2和多种肿瘤的侵袭性生物学行为相关。本研究中,我们探索肾癌术后EZH2的表达水平与肾癌临床病理特征和预后的相关性。方法：我们分析本研究所373例肾癌病人EZH2和H3K27me3的表达水平。通过Kaplan-Meier分析总生存期和无病生存期。应用Cox回归的方法分析EZH2和H3K27me3表达水平与预后的相关性。通过ROC曲线方法对预后预测准确性分析。结果：高表达水平的EZH2和肾癌不良预后相关,特别是进展期肾癌,可作为无病生存期和总生存期的独立预后因子。H3K27me3与EZH2相比,不能作为肾癌独立预后因子。H3K27me3表达水平和EZH2并不完全一致,可能与多梳抑制复合物2亚基间复杂的相互作用有关。联合EZH2表达水平和TNM分期无论对无病生存期还是总生存期的预测都优于单独应用EZH2或TNM分期。结论：肾癌中EZH2的表达水平可增强TNM分期系统对预后的预测,为晚期肾癌更好的个性化治疗提供新的方向。第二部分EZH2通过表观抑制E-cadherin促进肾癌的转移和侵袭目的：研究EZH2在肾癌发生发展中发挥作用的分子机制和临床意义。方法：免疫组化方法分析EZH2. H3K27me3和E-cadherin在257例肾癌病例中的表达水平。通过qRT-PCR, Western blot、染色质免疫共沉淀和免疫组化的方法检测EZH2对E-cadherin的调控。在肾癌细胞系中做迁移和侵袭实验。通过裸鼠行肾癌细胞皮下成瘤实验。结果：EZH2促进肾癌细胞迁移和侵袭的能力。通过shEZH2和小分子抑制剂DZNep沉默EZH2可抑制肾癌细胞迁移和侵袭的能力,上调E-cadherin的表达水平,抑制裸鼠皮下成瘤的增长,延长裸鼠生存期。EZH2的表达水平增高伴随E-cadherin表达抑制和肾癌进展分期相关并导致无瘤生存期和总生存期的不良预后。结论：EZH2有可能通过抑制E-cadherin促进肾癌的发生发展并成为进展期肾癌的潜在治疗靶点。
[Abstract]:Part one prospective study on the expression of EZH2 and its activity in renal cell carcinoma objective: it has been reported that EZH2 is associated with invasive biological behavior of various tumors. In this study, we investigated the correlation between the expression of EZH2 and clinicopathological features and prognosis of renal cell carcinoma. Methods: we analyzed the expression of EZH2 and H3K27me3 in 373 patients with renal cell carcinoma. Total survival and disease-free survival were analyzed by Kaplan-Meier. The correlation between the expression of EZH2 and H3K27me3 and prognosis was analyzed by Cox regression. The prediction accuracy of prognosis was analyzed by ROC curve method. Results: high expression of EZH2 was associated with poor prognosis of renal cell carcinoma, especially advanced renal cell carcinoma, which could be regarded as an independent prognostic factor of disease-free survival and total survival. H3K27me3 was compared with EZH2. The expression level of H3K27me3 is not consistent with that of EZH2, which may be related to the complex interaction between subunit 2 of multi-comb inhibitory complex. Combined EZH2 expression and TNM staging were superior to EZH2 or TNM staging in predicting disease-free survival or total survival. Conclusion: the expression of EZH2 in renal cell carcinoma can enhance the prognostic value of TNM staging system and provide a new direction for better individualized treatment of advanced renal cell carcinoma. The second part: EZH2 promotes the metastasis and invasion of renal cell carcinoma by inhibiting E-cadherin. Objective: to study the molecular mechanism and clinical significance of EZH2 in the pathogenesis and development of renal cell carcinoma. Methods: immunohistochemical analysis of EZH2. Expression of H3K27me3 and E-cadherin in 257 cases of renal cell carcinoma. The regulation of E-cadherin by EZH2 was detected by immunoprecipitation and immunohistochemistry of qRT-PCR, Western blot, chromatin. Migration and invasion were performed in renal cell line. The subcutaneous tumorigenesis of renal cancer cells was carried out in nude mice. Results: EZH2 promoted the ability of migration and invasion of renal cancer cells. Silencing EZH2 by shEZH2 and small molecule inhibitor DZNep can inhibit the ability of migration and invasion of renal cancer cells, up-regulate the expression of E-cadherin, and inhibit the growth of subcutaneous tumorigenesis in nude mice. The increased expression of EZH2 was associated with the inhibition of E-cadherin expression and the progression and staging of renal cell carcinoma, which led to the poor prognosis of tumor-free survival and total survival. Conclusion: EZH2 may promote the development of renal cell carcinoma by inhibiting E-cadherin and become a potential therapeutic target for advanced renal cell carcinoma.
【学位授予单位】：复旦大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R737.11

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