本文關(guān)鍵詞： 膠質(zhì)母細(xì)胞瘤 Hif-1α SP1 H19 低氧 PTEN　出處：《南京醫(yī)科大學(xué)》2017年博士論文　論文類型：學(xué)位論文

【摘要】：背景與目的:膠質(zhì)母細(xì)胞瘤是人類顱內(nèi)惡性程度最高的腫瘤之一,有著易復(fù)發(fā),難治愈的特點(diǎn)。而低氧狀態(tài)是腫瘤的關(guān)鍵病理特征,主要由于腫瘤細(xì)胞生長(zhǎng)速度快,與之相匹配的血管生成速度慢,局部組織的血液灌注出現(xiàn)障礙而導(dǎo)致局部低氧。膠質(zhì)母細(xì)胞瘤由于生長(zhǎng)速度快,常常導(dǎo)致中心區(qū)域血液供氧障礙,腫瘤組織形成壞死區(qū)。這其中低氧狀態(tài)一直是膠質(zhì)母細(xì)胞瘤中的普遍現(xiàn)象。近年來熱點(diǎn)研究顯示,低氧狀態(tài)對(duì)惡性腫瘤的發(fā)生發(fā)展起到了調(diào)控作用,它在促進(jìn)腫瘤進(jìn)展,諸如侵襲,轉(zhuǎn)移,血管增殖等方面,和腫瘤適應(yīng)低氧應(yīng)激環(huán)境方面都起到重要作用。目前已表明低氧狀態(tài)下的關(guān)鍵調(diào)節(jié)蛋白是低氧誘導(dǎo)因子-1復(fù)合物(Hif-1 complex),此復(fù)合物是一個(gè)異質(zhì)二聚體的轉(zhuǎn)錄因子,由低氧誘導(dǎo)因子-1α(Hif-1α)和低氧誘導(dǎo)因子-1β(Hif-1β)兩個(gè)亞單位組成。常氧狀態(tài)下,Hif-1α可被PHD蛋白羥基化后,經(jīng)VHL蛋白識(shí)別而使Hif-1α泛素化,經(jīng)由泛素-蛋白酶體系統(tǒng)快速降解,但低氧狀態(tài)下,PHD蛋白受到抑制,導(dǎo)致Hif-1α在細(xì)胞中積累,并與Hif-1β二聚化結(jié)合,形成活化的Hif-1復(fù)合物,并由胞質(zhì)轉(zhuǎn)入胞核內(nèi),在胞核內(nèi)結(jié)合于靶基因啟動(dòng)子區(qū)或增強(qiáng)子區(qū)上的低氧反應(yīng)元件(HRE,5'-RCGTG-3'),從而激活下游靶基因的轉(zhuǎn)錄。同時(shí)近年來越來越多的研究表明lncRNA和人類膠質(zhì)母細(xì)胞瘤的發(fā)生發(fā)展關(guān)系密切。一些lncRNA參與腫瘤低氧下的功能變化過程,在促腫瘤進(jìn)展和適應(yīng)低氧應(yīng)激環(huán)境中都起到潛在作用。這其中l(wèi)ncRNA H19作為較早一批被發(fā)現(xiàn)的lncRNA,在許多腫瘤中都高表達(dá),并與腫瘤的周期、侵襲、凋亡和增殖等活動(dòng)密切相關(guān)。先前研究發(fā)現(xiàn),低氧下H19表達(dá)有所增加,但具體機(jī)制不明。本文就旨在探討低氧對(duì)H19調(diào)控的具體機(jī)制,通過轉(zhuǎn)錄因子Hif-1α直接調(diào)控和間接調(diào)控兩種途徑與H19啟動(dòng)子區(qū)結(jié)合,激活其DNA轉(zhuǎn)錄過程,使得膠質(zhì)母細(xì)胞瘤中H19過表達(dá),從而影響膠質(zhì)瘤細(xì)胞的惡性功能表型。這項(xiàng)研究為H19作為膠質(zhì)瘤診斷和治療靶點(diǎn)提供了理論依據(jù),并為當(dāng)下熱門的低氧下調(diào)控lncRNA的機(jī)制研究提供了參考,為腫瘤進(jìn)展中的分子調(diào)控機(jī)制研究提供了一個(gè)新的啟示和研究方向。研究方法:1 人膠質(zhì)瘤mRNA的芯片表達(dá)數(shù)據(jù)以及患者的生存數(shù)據(jù)均下載于美國(guó)癌癥基因組圖譜數(shù)據(jù)庫(TCGA)官網(wǎng)。2 LncRNA熒光定量PCR采用SYBR Green PCR反應(yīng)體系和TaqMan反應(yīng)體系。利用物理低氧方式建立不同低氧時(shí)間段的各種膠質(zhì)瘤細(xì)胞系,利用熒光定量PCR技術(shù)檢測(cè)H19在這些不同時(shí)間節(jié)點(diǎn)的細(xì)胞中表達(dá)情況。3 利用質(zhì)�；蛐「蓴_RNA建立過表達(dá)或低表達(dá)Hif-1α的膠質(zhì)瘤U87和U251細(xì)胞系,利用熒光定量PCR技術(shù)檢測(cè)H19在這些U87和U251細(xì)胞系中的相對(duì)表達(dá)量。另外,通過裸鼠原位成瘤模型驗(yàn)證體內(nèi)試驗(yàn)中也存在Hif-1α對(duì)H19表達(dá)的調(diào)控作用。4 通過熒光定量PCR和Western blot實(shí)驗(yàn)驗(yàn)證各種細(xì)胞中PTEN狀態(tài)對(duì)于低氧下H19表達(dá)上調(diào)的敏感性影響,以及PTEN通過影響低氧下Hif-1α穩(wěn)定性參與到低氧調(diào)控H19的表達(dá)這一過程中。5 運(yùn)用熒光定量PCR和Western blot實(shí)驗(yàn)驗(yàn)證22例人腦膠質(zhì)瘤組織樣本中Hif-1α與H19的相關(guān)性,以及PTEN對(duì)這種Hif-1α與H19的相關(guān)性的影響。用免疫組化和原位雜交技術(shù)檢測(cè)正常組織和膠質(zhì)瘤組織中Hif-1α與H19的表達(dá)差異。6 生物信息學(xué)預(yù)測(cè)、染色質(zhì)免疫共沉淀(ChIP)實(shí)驗(yàn),熒光素酶報(bào)告實(shí)驗(yàn)、熒光定量PCR和Western blot實(shí)驗(yàn)驗(yàn)證Hif-1α對(duì)H19啟動(dòng)子區(qū)的靶向關(guān)系以及Hif-1α調(diào)控的SP1對(duì)H19啟動(dòng)子區(qū)的轉(zhuǎn)錄調(diào)控。7 取對(duì)數(shù)生長(zhǎng)期的U87和U251細(xì)胞,通過體外劃痕和Transwell實(shí)驗(yàn)檢測(cè)H19對(duì)于低氧下膠質(zhì)瘤細(xì)胞遷移侵襲生物學(xué)行為的變化。8 生物信息學(xué)預(yù)測(cè),熒光素酶報(bào)告實(shí)驗(yàn)、熒光定量PCR和Western blot實(shí)驗(yàn)驗(yàn)證H19通過吸附miRNA-181d對(duì)β-catenin蛋白的影響。研究結(jié)果:1 低氧環(huán)境下在U87和U251細(xì)胞中,H19表達(dá)量隨低氧時(shí)間的延長(zhǎng)而逐步升高。同時(shí)低氧中過表達(dá)Hif-1α后,H19表達(dá)較對(duì)照組有所上升,而敲低Hif-1α表達(dá)后,H19在低氧環(huán)境中的上調(diào)較對(duì)照組明顯降低。在裸鼠原位成瘤模型中,體內(nèi)實(shí)驗(yàn)也驗(yàn)證了上調(diào)Hif-1α表達(dá)可以促H19的表達(dá)。2 在不同膠質(zhì)瘤細(xì)胞系中,表達(dá)PTEN野生型的Ln229細(xì)胞系和原代培養(yǎng)的PG1細(xì)胞系,H19對(duì)于低氧刺激的表達(dá)上調(diào)不敏感;而在PTEN缺失或者突變表達(dá)的U87,U251,U118,U373細(xì)胞系和原代培養(yǎng)的PG2細(xì)胞中,低氧可以顯著有效地促H19表達(dá)上調(diào)。而通過回復(fù)實(shí)驗(yàn),則PTEN野生的Ln229細(xì)胞和PTEN缺失的U87細(xì)胞均有H19對(duì)低氧反應(yīng)的改變。這與細(xì)胞中的PTEN影響Hif-1α蛋白穩(wěn)定性有關(guān)。3 在人15例正常腦組織和22例膠質(zhì)母瘤細(xì)胞組織中,Hif-1α與H19均在腫瘤組織中較正常組織高表達(dá),它們的表達(dá)量互相呈正相關(guān)。而組織樣本中的PTEN狀態(tài)可以影響Hif-1α與H19之間的正相關(guān)程度。4 生物信息學(xué)、染色質(zhì)免疫共沉淀實(shí)驗(yàn),熒光素酶報(bào)告基因?qū)嶒?yàn)和western blot研究表明:Hif-1α可以與H19啟動(dòng)子區(qū)內(nèi)的低氧反應(yīng)元件序列HRE(5'-acgtg-3')結(jié)合,從而促進(jìn)H19的轉(zhuǎn)錄,但即便HRE序列全部突變情況下,熒光素酶仍然有變化,表明Hif-1α也可以通過其它途徑影響H19的轉(zhuǎn)錄。5 SP1已被報(bào)道可被Hif-1α結(jié)合于SP1的啟動(dòng)子區(qū),從而促進(jìn)自身的轉(zhuǎn)錄。生物信息學(xué)、染色質(zhì)免疫共沉淀實(shí)驗(yàn),熒光素酶報(bào)告基因?qū)嶒?yàn)和western blot研究表明:SP1也可以作用于H19啟動(dòng)子區(qū)促進(jìn)H19的轉(zhuǎn)錄。體外和體內(nèi)實(shí)驗(yàn)均證實(shí)SP1可以調(diào)控H19表達(dá),回復(fù)實(shí)驗(yàn)證明SP1是Hif-1α調(diào)控H19反應(yīng)中不可缺少的中間一環(huán)。6 體外劃痕和Transwell實(shí)驗(yàn)證明H19在低氧對(duì)膠質(zhì)瘤細(xì)胞遷移侵襲功能中起到一定作用,同時(shí)H19也是低氧調(diào)控EMT相關(guān)蛋白的重要中介者。7 生物信息學(xué)預(yù)測(cè)和熒光素酶報(bào)告基因?qū)嶒?yàn)提示H19可吸附miRNA-181d來調(diào)控α-catenin蛋白翻譯水平,從而參與到腫瘤相關(guān)惡性功能改變中來。研究結(jié)論:1 膠質(zhì)母細(xì)胞瘤細(xì)胞中低氧狀態(tài)可以影響H19的含量,主要是通過Hif-1α來調(diào)控H19的轉(zhuǎn)錄水平來實(shí)現(xiàn)。而腫瘤細(xì)胞的PTEN狀態(tài)是低氧對(duì)于H19刺激上調(diào)的阻撓因素。2 Hif-1α可以自身直接結(jié)合于與H19啟動(dòng)子區(qū),促進(jìn)H19轉(zhuǎn)錄;也可以通過促進(jìn)SP1蛋白水平表達(dá)升高,而SP1也可以結(jié)合于H19啟動(dòng)子區(qū),促進(jìn)其轉(zhuǎn)錄水平升高。3 膠質(zhì)母細(xì)胞瘤中異常表達(dá)的H19,可以吸附miRNA-181d,減少miRNA-181d對(duì)β-catenin的翻譯抑制作用,最終促進(jìn)β-catenin蛋白水平上升,調(diào)控其相關(guān)EMT蛋白,有助于低氧狀態(tài)下增強(qiáng)腫瘤遷移侵襲能力。
[Abstract]:Background and objective: glioblastoma is one of the most malignant tumors in human brain, with features of easy to relapse, difficult to cure. Hypoxia is a key pathological feature of cancer, mainly due to faster tumor cell growth, angiogenesis speed to match the slow, local tissue blood perfusion obstacle lead to local hypoxia. Glioblastoma due to fast growth, often leading to central region of the blood oxygen barrier, the formation of necrosis of tumor tissue. The hypoxia has been a common phenomenon in glioblastoma. Display the hot research in recent years, hypoxia on malignant tumor occurrence and development play a role in it. Tumor progression, such as metastasis, vascular invasion, proliferation, and tumor adaptation of hypoxia stress environment play an important role. Now that the key under hypoxia regulation Protein is a hypoxia inducible factor -1 complex (Hif-1 complex), the compound is a transcription factor hetero dimerization of two by hypoxia inducible factor -1 alpha (Hif-1 alpha) and hypoxia inducible factor -1 beta (Hif-1 beta) two subunits. Under normoxic condition, Hif-1 alpha by PHD protein hydroxyl after the VHL protein identification and Hif-1 alpha ubiquitination, rapid degradation via the ubiquitin proteasome system, but under hypoxia condition, PHD protein was inhibited, leading to Hif-1 accumulation in the alpha cells, and combined with the Hif-1 beta dimerization, activation of the Hif-1 complex formation, and transferred from cytoplasm and nucleus in binding to the target gene promoter or enhancer promoter hypoxia response element region in nuclei (HRE, 5'-RCGTG-3'), thereby activating the transcription of downstream target genes. At the same time, in recent years, more and more studies show that lncRNA and human glioblastoma is closely related to the occurrence and development of lncRNA in some. Function changes during tumor hypoxia, in promoting tumor progression and adaptation to hypoxia stress environment plays a potential role. The lncRNA H19 as one of the earliest a batch of lncRNA was found in many tumors, high expression and tumor cycle, invasion, apoptosis and proliferation activities are closely related to the previous study. Found that the expression of H19 under hypoxia increased, but the mechanism is unclear. This paper aims to explore the specific mechanism of hypoxia on the regulation of H19 transcription factor Hif-1 alpha, through a combination of direct control and indirect control in two ways with the promoter region of H19, activation of the DNA transcription process makes glioblastoma H19 expression, thus effect of function of malignant phenotype of glioma cells. This study provides a theoretical basis for the diagnosis and treatment of glioma as targets for H19, and offer the reference for research on the mechanism of regulation of lncRNA hypoxia hot current, tumor Provides a new enlightenment and research progress in molecular mechanism. Methods: 1 human glioma mRNA microarray expression data and survival data were downloaded from the database of the Cancer Genome Atlas (TCGA) official website of.2 LncRNA fluorescence quantitative PCR using SYBR Green PCR reaction and TaqMan reaction system. Glioma cell line using physical hypoxia establish different hypoxia time, the expression of U87 and U251 glioma cell lines of plasmid or small disturbance using.3 RNA to establish the expression or low expression of Hif-1 alpha by fluorescence quantitative PCR detection of H19 in these cells in different time points, the relative expression by fluorescence quantitative PCR detection H19 in the U87 and U251 cell lines in nude mice by weight. In addition, in situ regulation of.4 Hif-1 alpha on the expression of H19 also exist in vivo tumor model validation The sensitivity of PTEN status and Western blot fluorescence quantitative PCR experiments in various cells under hypoxia on the expression of H19, Hif-1 and PTEN by alpha stability under hypoxia effects involved in the regulation of H19 expression of hypoxia in the process of.5 using fluorescence quantitative PCR and Western blot experiments to verify the relevance of 22 cases of Hif-1 human glioma tissue samples. Alpha and H19, as well as the influence on the correlation between PTEN and H19. The Hif-1 alpha assay were used to detect Hif-1 expression differences and in situ hybridization in normal tissues and glioma tissues and alpha H19.6 bioinformatics prediction, chromatin immunoprecipitation (ChIP) experiments, luciferase reporter assay, fluorescence quantitative PCR Western and blot experiments on Hif-1 alpha H19 promoter targeting and regulation of SP1 on Hif-1 alpha H19 promoter transcriptional regulation of.7 in logarithmic growth phase U87 and U251 The changes of.8 cells, prediction of biological information in vitro scratch and Transwell assay for H19 glioma cell migration and invasion under hypoxia biological behavior, luciferase reporter assay, fluorescence quantitative PCR and Western blot experiments to verify the H19 effect on beta -catenin protein by adsorption of miRNA-181d. Results: 1 under hypoxia in U87 and U251 cells the expression of H19, with the extension of hypoxic time gradually increased. At the same time hypoxia over expression of Hif-1 alpha, H19 expression increased compared with the control group, while knockdown Hif-1 protein alpha, H19 in hypoxia environment increased significantly lower than the control group. In the orthotopic tumor model in vivo is verified by the experiment upregulation of Hif-1 expression can promote expression of.2 H19 in different glioma cell line, PG1 cell line Ln229 cells expressing wild-type PTEN and cultured for H19, the expression of hypoxia To adjust the sensitivity; while in PTEN deletions or mutations on the expression of U87, U251, U118, U373 cell lines and primary cultured PG2 cells, hypoxia can significantly promote H19 expression. The recovery test, PTEN wild Ln229 cells and PTEN U87 cells absence of H19 were of low oxygen reaction this change. And the effects of PTEN cells in the Hif-1 protein stability of.3 in 15 cases of normal brain tissues and 22 cases of glioma tissues, Hif-1 alpha and H19 in tumor tissues was higher than that in normal tissues, their expression levels were positively correlated with each other. The tissue samples in the PTEN state can be positive the degree of correlation between the effects of.4 biological information Hif-1 alpha and H19, chromatin immunoprecipitation experiments, luciferase reporter assay and Western blot study showed that Hif-1 and H19 can start a hypoxia response element sequence HRE sub region (5'-acgtg-3'). Together, so as to promote the transcription of H19, but even HRE sequence all mutation, luciferase still have showed Hif-1 changes, can also affect the transcription of H19.5 SP1 through other ways have been reported to be the promoter region of Hif-1 in combination with SP1, so as to promote their own transcription. Bio Informatics, chromatin co immunoprecipitation experiments, luciferase reporter assay and Western blot study showed that SP1 can also act on the transcription of H19 promoter region to promote H19. In vitro and in vivo experiments have demonstrated that SP1 can regulate the expression of H19, recovery experiments prove that SP1 is an intermediate Hif-1 alpha control indispensable H19 reaction in a ring of.6 and Transwell in vitro scratch experiment H19 in hypoxia on glioma cell migration plays a certain role in the invasion of important intermediary function, regulation of EMT related protein H19 at the same time, hypoxia.7 bioinformatics prediction and Luciferase Report The experiment showed that the H19 gene can be adsorbed miRNA-181d to regulate -catenin protein translation level, which involved in the change of tumor associated malignant function. Conclusions: 1 hypoxic glioblastoma cells can influence the content of H19, mainly through the transcriptional level of Hif-1 alpha to control H19 to achieve. The tumor cell PTEN the state is hypoxia to thwart factors of.2 Hif-1 alpha H19 stimulated upregulation can directly bind to the promoter region of H19 and H19, to promote transcription; can also be increased by promoting the expression of SP1 protein levels, SP1 can also bind to H19 promoter, promote the transcription level increased expression of.3 in glioblastoma H19 can reduce the adsorption of miRNA-181d, miRNA-181d, -catenin on beta translation inhibition, ultimately promote beta -catenin protein levels increased, the regulation of EMT protein, contributes to enhanced tumor hypoxia Migration and invasion ability.

【學(xué)位授予單位】：南京醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R739.41

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