低氧微环境下SPOP蛋白促进肾癌发生的作用机制研究

发布时间：2018-06-02 05:57

本文选题：SPOP + PTEN　；参考：《中国科学院北京基因组研究所》2014年博士论文

【摘要】：低氧环境压力和低氧诱导因子HIF在许多肿瘤中发挥重要功能。肿瘤细胞可以通过许多方式来适应低氧微环境以促进肿瘤生长。肾透明细胞癌(clear cell Renal Cell Carcinoma, ccRCC)是最为常见的肾癌类型,约占75-85%。ccRCC相比其他肿瘤更适应低氧微环境,因此是研究肿瘤低氧微环境适应性的重要模型。肾癌早期症状不明显,待发现时常已发生转移。肾癌对放疗及化疗不敏感,转移后肿瘤的免疫疗法效果有限且副作用大。近年来,虽然针对VEGF、PDGF及mTOR等HIF下游等信号通路的肾癌靶向药物研发取得了一些进展,但对晚期肾癌效果仍非常有限。因此,急需更进一步了解肾癌的发病机制及其对低氧微环境的适应机制,以便寻找更加有效的药物靶点。E3泛素连接酶Cul3的底物接头蛋白SPOP在99%的肾透明细胞癌中过表达,是肾透明细胞癌的生物标记。本课题旨在研究SPOP蛋白过表达是否参与肾癌形成及其可能的作用机制。我们发现,在肾癌中低氧诱导因子HIF可以在转录水平调控SPOP表达。VHL功能的缺失导致了HIF过度活化,进而导致了SPOP过表达。过表达的SPOP蛋白在肾癌细胞质中大量累积。低氧诱导是导致SPOP蛋白在细胞质中累积的原因。累积到细胞质中的SPOP可以促进细胞增殖和肿瘤形成。细胞质中SPOP可以与肿瘤抑制因子PTEN以及ERK磷酸酶DUSP7结合,介导了对PTEN和DUSP7的泛素化降解,从而激活了PI3K-Akt和ERK信号通路。此外,肾癌中SPOP还通过降解Daxx和Gli2来抑制细胞凋亡和促进细胞增殖。肾癌病例标本中这些底物的蛋白水平与SPOP呈相反的关系,进一步说明病理情况下肾癌中SPOP通过降解这些底物促进了肿瘤的形成。以上结果阐明了SPOP在促进ccRCC形成中的重要机制,即作为一个关键枢纽蛋白连接了低氧应激反应和泛素化降解肿瘤抑制因子。肾癌中SPOP的原癌基因功能让其成为治疗肾癌一个新的、更加特异的药物靶点。
[Abstract]:Hypoxic environmental pressure and hypoxia inducible factor HIF play an important role in many tumors. Tumor cells can adapt to low oxygen microenvironments in many ways to promote tumor growth. Clear cell Renal Cell Carcinoma (ccRCC) is the most common type of renal cancer, accounting for less adaptation to 75-85%.ccRCC than other tumors. Oxygen microenvironment is an important model for the study of the adaptability of tumor hypoxic microenvironment. The early symptoms of renal carcinoma are not obvious, and metastasis is often found. Renal cancer is insensitive to radiotherapy and chemotherapy. The effect of immunotherapy after metastasis is limited and side effects are great. In recent years, the renal cancer of VEGF, PDGF and mTOR and other HIF downstream signal pathways Some progress has been made in targeted drug development, but the effect of advanced renal cancer is still very limited. Therefore, it is urgent to understand the pathogenesis of renal cancer and its adaptation mechanism to the hypoxia microenvironment so as to find a more effective drug target.E3 ubiquitin ligase Cul3 substrate joint protein SPOP in 99% renal clear cell carcinoma. It is a biomarker for renal clear cell carcinoma. The aim of this study is to investigate whether SPOP protein overexpression is involved in the pathogenesis of renal cell carcinoma and its possible mechanism.
We found that in renal cancer, hypoxia inducible factor HIF can regulate the deletion of SPOP expression.VHL at transcriptional level, resulting in overactivation of HIF, leading to SPOP overexpression. The overexpressed SPOP protein accumulates in the cytoplasm of renal cancer. Hypoxia induction is the cause of the accumulation of SPOP protein in the cytoplasm. The accumulation of S in the cytoplasm. POP can promote cell proliferation and tumor formation. In cytoplasm, SPOP can bind to tumor suppressor PTEN and ERK phosphatase DUSP7, mediate the ubiquitination of PTEN and DUSP7, and thus activate PI3K-Akt and ERK signaling pathways. In addition, SPOP also inhibits apoptosis and promotes cell proliferation by degradation of Daxx and Gli2. The protein level of these substrates in cancer cases is opposite to SPOP, which further illustrates that in the pathological conditions, SPOP can promote the formation of tumor by degradation of these substrates. The above results illustrate the important mechanism of SPOP in promoting the formation of ccRCC, that is, as a key pivot protein, it connects hypoxia stress response and ubiquitination. The proto oncogene function of SPOP in renal cell carcinoma has made it a new and more specific drug target for the treatment of renal cell carcinoma.
【学位授予单位】：中国科学院北京基因组研究所
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R737.11

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