本文選題：SPOP + PTEN　； 參考：《中國科學院北京基因組研究所》2014年博士論文

【摘要】：低氧環(huán)境壓力和低氧誘導因子HIF在許多腫瘤中發(fā)揮重要功能。腫瘤細胞可以通過許多方式來適應低氧微環(huán)境以促進腫瘤生長。腎透明細胞癌(clear cell Renal Cell Carcinoma, ccRCC)是最為常見的腎癌類型,約占75-85%。ccRCC相比其他腫瘤更適應低氧微環(huán)境,因此是研究腫瘤低氧微環(huán)境適應性的重要模型。腎癌早期癥狀不明顯,待發(fā)現(xiàn)時常已發(fā)生轉(zhuǎn)移。腎癌對放療及化療不敏感,轉(zhuǎn)移后腫瘤的免疫療法效果有限且副作用大。近年來,雖然針對VEGF、PDGF及mTOR等HIF下游等信號通路的腎癌靶向藥物研發(fā)取得了一些進展,但對晚期腎癌效果仍非常有限。因此,急需更進一步了解腎癌的發(fā)病機制及其對低氧微環(huán)境的適應機制,以便尋找更加有效的藥物靶點。E3泛素連接酶Cul3的底物接頭蛋白SPOP在99%的腎透明細胞癌中過表達,是腎透明細胞癌的生物標記。本課題旨在研究SPOP蛋白過表達是否參與腎癌形成及其可能的作用機制。 我們發(fā)現(xiàn),在腎癌中低氧誘導因子HIF可以在轉(zhuǎn)錄水平調(diào)控SPOP表達。VHL功能的缺失導致了HIF過度活化,進而導致了SPOP過表達。過表達的SPOP蛋白在腎癌細胞質(zhì)中大量累積。低氧誘導是導致SPOP蛋白在細胞質(zhì)中累積的原因。累積到細胞質(zhì)中的SPOP可以促進細胞增殖和腫瘤形成。細胞質(zhì)中SPOP可以與腫瘤抑制因子PTEN以及ERK磷酸酶DUSP7結(jié)合,介導了對PTEN和DUSP7的泛素化降解,從而激活了PI3K-Akt和ERK信號通路。此外,腎癌中SPOP還通過降解Daxx和Gli2來抑制細胞凋亡和促進細胞增殖。腎癌病例標本中這些底物的蛋白水平與SPOP呈相反的關(guān)系,進一步說明病理情況下腎癌中SPOP通過降解這些底物促進了腫瘤的形成。以上結(jié)果闡明了SPOP在促進ccRCC形成中的重要機制,即作為一個關(guān)鍵樞紐蛋白連接了低氧應激反應和泛素化降解腫瘤抑制因子。腎癌中SPOP的原癌基因功能讓其成為治療腎癌一個新的、更加特異的藥物靶點。
[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.
【學位授予單位】：中國科學院北京基因組研究所
【學位級別】：博士
【學位授予年份】：2014
【分類號】：R737.11

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本文編號：1967676