本文選題：SPOP + PTEN　； 參考：《中國(guó)科學(xué)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(dǎo)因子HIF在許多腫瘤中發(fā)揮重要功能。腫瘤細(xì)胞可以通過(guò)許多方式來(lái)適應(yīng)低氧微環(huán)境以促進(jìn)腫瘤生長(zhǎng)。腎透明細(xì)胞癌(clear cell Renal Cell Carcinoma, ccRCC)是最為常見(jiàn)的腎癌類(lèi)型,約占75-85%。ccRCC相比其他腫瘤更適應(yīng)低氧微環(huán)境,因此是研究腫瘤低氧微環(huán)境適應(yīng)性的重要模型。腎癌早期癥狀不明顯,待發(fā)現(xiàn)時(shí)常已發(fā)生轉(zhuǎn)移。腎癌對(duì)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(lái),雖然針對(duì)VEGF、PDGF及mTOR等HIF下游等信號(hào)通路的腎癌靶向藥物研發(fā)取得了一些進(jìn)展,但對(duì)晚期腎癌效果仍非常有限。因此,急需更進(jìn)一步了解腎癌的發(fā)病機(jī)制及其對(duì)低氧微環(huán)境的適應(yīng)機(jī)制,以便尋找更加有效的藥物靶點(diǎn)。E3泛素連接酶Cul3的底物接頭蛋白SPOP在99%的腎透明細(xì)胞癌中過(guò)表達(dá),是腎透明細(xì)胞癌的生物標(biāo)記。本課題旨在研究SPOP蛋白過(guò)表達(dá)是否參與腎癌形成及其可能的作用機(jī)制。 我們發(fā)現(xiàn),在腎癌中低氧誘導(dǎo)因子HIF可以在轉(zhuǎn)錄水平調(diào)控SPOP表達(dá)。VHL功能的缺失導(dǎo)致了HIF過(guò)度活化,進(jìn)而導(dǎo)致了SPOP過(guò)表達(dá)。過(guò)表達(dá)的SPOP蛋白在腎癌細(xì)胞質(zhì)中大量累積。低氧誘導(dǎo)是導(dǎo)致SPOP蛋白在細(xì)胞質(zhì)中累積的原因。累積到細(xì)胞質(zhì)中的SPOP可以促進(jìn)細(xì)胞增殖和腫瘤形成。細(xì)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(dǎo)了對(duì)PTEN和DUSP7的泛素化降解,從而激活了PI3K-Akt和ERK信號(hào)通路。此外,腎癌中SPOP還通過(guò)降解Daxx和Gli2來(lái)抑制細(xì)胞凋亡和促進(jìn)細(xì)胞增殖。腎癌病例標(biāo)本中這些底物的蛋白水平與SPOP呈相反的關(guān)系,進(jìn)一步說(shuō)明病理情況下腎癌中SPOP通過(guò)降解這些底物促進(jìn)了腫瘤的形成。以上結(jié)果闡明了SPOP在促進(jìn)ccRCC形成中的重要機(jī)制,即作為一個(gè)關(guān)鍵樞紐蛋白連接了低氧應(yīng)激反應(yīng)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(gè)新的、更加特異的藥物靶點(diǎn)。
[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(xué)位授予單位】：中國(guó)科學(xué)院北京基因組研究所
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類(lèi)號(hào)】：R737.11

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本文編號(hào)：1967676