發(fā)布時間：2018-06-30 06:02

  本文選題：NNMT + 膠質(zhì)瘤�。� 參考：《第二軍醫(yī)大學(xué)》2016年博士論文

【摘要】：腦膠質(zhì)瘤是中樞神經(jīng)系統(tǒng)最常見的惡性腫瘤之一,約占全部腦腫瘤的45～55%。目前,腦膠質(zhì)瘤的治療手段主要包括手術(shù)治療、放射治療、化學(xué)治療等,但由于腫瘤呈浸潤性生長,與周圍腦組織無明顯分界且易于復(fù)發(fā),上述傳統(tǒng)治療措施療效均不甚理想。新的治療手段如基因治療等雖有望成為治愈膠質(zhì)瘤的途徑之一,但目前仍缺乏理想可靠的治療靶標(biāo)。因此尋找調(diào)控膠質(zhì)瘤細(xì)胞惡性生物學(xué)行為的分子靶標(biāo),明確其在膠質(zhì)瘤發(fā)病過程中的病理機(jī)理,已成為神經(jīng)科學(xué)領(lǐng)域的研究熱點(diǎn)之一。煙酰胺N-甲基轉(zhuǎn)移酶NNMT是一種S-腺苷基-L-甲硫氨酸依賴性細(xì)胞質(zhì)酶,催化煙酰胺及其它嘧啶的N-甲基單元,形成吡啶離子。NNMT在肝臟組織中有明顯的表達(dá),而在腎臟、肺臟、骨骼肌、胎盤、心臟等很少表達(dá),在腦組織中低表達(dá)或不表達(dá)。目前研究發(fā)現(xiàn),NNMT在多種腫瘤組織中異常表達(dá),包括:胃腺癌、甲狀腺乳頭狀癌、結(jié)腸癌、肝細(xì)胞癌、肺癌、胰腺癌等。在非腫瘤性病變中,NNMT被發(fā)現(xiàn)在慢性阻塞性肺疾病COPD、動脈粥樣硬化、以及帕金森病中異常表達(dá)。NNMT參與腫瘤的代謝、甲基化、氧化應(yīng)激反應(yīng),被認(rèn)為在腫瘤的發(fā)生、發(fā)展中產(chǎn)生重要作用,但其具體機(jī)制尚不清楚。Kristian Ovaska等通過大數(shù)據(jù)框架整合技術(shù)Anduril,整合大規(guī)模分子及臨床數(shù)據(jù),分析篩選出一組與GBM增殖、生存以及多形性密切相關(guān)的基因改變,NNMT基因便是其中之一,初步發(fā)現(xiàn)在體外細(xì)胞中下調(diào)NNMT的表達(dá)可以顯著抑制GBM的增殖,提示NNMT可能在膠質(zhì)瘤的惡性生物學(xué)行為中扮演重要角色,但具體機(jī)制尚無研究。我們將從以下幾個方面對NNMT在膠質(zhì)瘤中的作用做系統(tǒng)的研究:制備了59例經(jīng)手術(shù)切除的膠質(zhì)瘤標(biāo)本組織芯片,通過Western blot檢測不同級別腦膠質(zhì)瘤中NNMT的表達(dá)水平。制作生存曲線,觀察NNMT表達(dá)水平與患者生存時間的關(guān)系。接著,進(jìn)行體外細(xì)胞學(xué)實(shí)驗(yàn),通過慢病毒敲減膠質(zhì)瘤細(xì)胞系中NNMT的表達(dá),檢測其對膠質(zhì)瘤細(xì)胞增殖、遷移、侵襲、凋亡等細(xì)胞惡性成為學(xué)行為的影響。通過成球?qū)嶒?yàn),觀察NNMT對膠質(zhì)瘤干性的影響。隨后,進(jìn)行差異基因表達(dá)譜芯片檢測,篩選NNMT基因下游靶標(biāo)基因。由于NNMT是甲基化調(diào)控酶,我們還將進(jìn)行甲基化檢測,闡明NNMT甲基化調(diào)控靶標(biāo)。最后,對NNMT調(diào)控下游靶標(biāo)的方式做出初步研究,從而闡明NNMT促進(jìn)膠質(zhì)瘤增殖、侵襲的作用機(jī)制。本實(shí)驗(yàn)將分四個部分進(jìn)行:1.NNMT在人腦膠質(zhì)瘤中的表達(dá)及臨床意義;2.NNMT對膠質(zhì)瘤增殖、侵襲、凋亡等細(xì)胞功能及干性的影響;3.NNMT在膠質(zhì)瘤中的下游靶標(biāo)篩選及驗(yàn)證;4.NNMT是否通過表觀遺傳調(diào)控促進(jìn)價(jià)膠質(zhì)瘤增殖侵襲。第一部分NNMT在人腦膠質(zhì)瘤中的表達(dá)及臨床意義研究目的:探討NNMT在膠質(zhì)瘤中的表達(dá)情況及臨床意義研究內(nèi)容:對59例經(jīng)手術(shù)切除的膠質(zhì)瘤標(biāo)本制作組織芯片,免疫組織化學(xué)檢測NNMT在不同級別膠質(zhì)瘤中的表達(dá)情況,同時對患者的隨訪資料進(jìn)行分析,分析NNMT在不同級別膠質(zhì)瘤中的表達(dá)情況與生存時間的關(guān)系,制作生存曲線。結(jié)果:NNMT在膠質(zhì)瘤中過表達(dá),其表對水平隨著病理級別的增加而增加,與膠質(zhì)瘤患者生存時間負(fù)相關(guān),NNMT表達(dá)高的患者,生存時間縮短。結(jié)論:NNMT在人腦膠質(zhì)瘤中過表達(dá),表達(dá)水平與膠質(zhì)瘤惡性程度正相關(guān),與生存時間負(fù)相關(guān),NNMT與膠質(zhì)瘤的惡性行為相關(guān)。第二部分NNMT對膠質(zhì)瘤增殖、侵襲、凋亡等細(xì)胞功能及干性的影響研究目的:體外細(xì)胞學(xué)實(shí)驗(yàn)研究NNMT對膠質(zhì)瘤細(xì)胞系增殖、遷移、侵襲、凋亡等細(xì)胞功能及成球能力等干性的影響研究內(nèi)容:構(gòu)建經(jīng)慢病毒轉(zhuǎn)染SiRNA敲減NNMT的U87、U251細(xì)胞系,同時設(shè)立空白對照組,篩選穩(wěn)轉(zhuǎn)細(xì)胞株。Western blot驗(yàn)證慢病毒敲減效果,WST1法檢測細(xì)胞增殖,劃痕法檢測細(xì)胞遷移,Transwell法檢測細(xì)胞侵襲,流式細(xì)胞儀檢測細(xì)胞凋亡,成球檢測NNMT對干性的影響。結(jié)果:慢病毒轉(zhuǎn)染SiRNA敲減NNMT后,U87、U251膠質(zhì)瘤細(xì)胞的增殖、遷移、侵襲能力明顯下降,成球能力下降,凋亡增加。結(jié)論:慢病毒轉(zhuǎn)染SiRNA敲減NNMT在U87、U251膠質(zhì)瘤細(xì)胞中的表達(dá),能抑制膠質(zhì)瘤細(xì)胞的增殖、遷移、凋亡等惡性表型,同時抑制成球能力(干性),并促進(jìn)腫瘤細(xì)胞凋亡。第三部分NNMT在膠質(zhì)瘤中的下游靶標(biāo)篩選及驗(yàn)證研究目的:篩選NNMT促進(jìn)膠質(zhì)瘤細(xì)胞增殖、侵襲等惡性生物學(xué)行為的下游靶標(biāo)基因。研究內(nèi)容:構(gòu)建慢病毒轉(zhuǎn)染SiRNA敲減U251細(xì)胞系兩組(U251-KD1,U251-KD2),同時設(shè)立空白對照組,篩選穩(wěn)轉(zhuǎn)細(xì)胞株。用基因表達(dá)譜芯片篩選下游靶標(biāo)基因。對篩選出的基因進(jìn)行作用分析,挑選感興趣基因。PCR及Western Blot驗(yàn)證靶標(biāo)基因。結(jié)果:U251-KD1和U251-KD2兩個NNMT敲減細(xì)胞系和U251-NC對比,進(jìn)行基因表達(dá)譜芯片分析,篩選出共同下調(diào)的基因共61個下調(diào)和32上調(diào)基因,進(jìn)一步分析挑選出感興趣的8個下調(diào)基因MMP2、MMP7、RSP03、SEMA3F、TNFRSF19、ANXA8、APOBEC3G、CXCR7,這8個基因與腫瘤的增殖、侵襲密切相關(guān)。同時挑選出5個上調(diào)基因PAK3、GAP43、ELAVL2、NEGR1、STAU2,這五個基因具有不同途徑的抑癌作用。對篩選出的靶標(biāo)基因進(jìn)行PCR驗(yàn)證,PCR結(jié)果與基因表達(dá)譜芯片篩選出的結(jié)果一致。結(jié)論:NNMT在U251膠質(zhì)瘤細(xì)胞中的下游上調(diào)靶標(biāo)基因MMP2、MMP7、RSP03、SEMA3F、TNFRSF19、ANXA8、APOBEC3G、CXCR7等主要與增殖、侵襲、遷移相關(guān),下游下調(diào)靶標(biāo)主要與PAK3、GAP43、ELAVL2、NEGR1、STAU2抑癌相關(guān)。第四部分 NNMT是否通表觀遺傳調(diào)控促進(jìn)膠質(zhì)瘤增殖侵襲研究目的:初步探討NNMT是否通過調(diào)控GAP-43促進(jìn)膠質(zhì)瘤的增殖、侵襲和凋亡。研究內(nèi)容:構(gòu)建慢病毒轉(zhuǎn)染SiRNA敲減NNMT U251細(xì)胞系兩組(U251-KD1,U251-KD2),同時設(shè)立空白對照組,篩選穩(wěn)轉(zhuǎn)細(xì)胞株。用甲基化芯片篩選下游作用靶標(biāo)。對篩選出的基因進(jìn)行文獻(xiàn)學(xué)習(xí),挑選感興趣基因。結(jié)果:慢病毒轉(zhuǎn)染SiRNA敲減NNMT U251細(xì)胞系兩組(U251-KD1,U251-KD2),引起GAP-43的多個甲基化位點(diǎn)發(fā)生變化,GAP-43也是我們在基因表達(dá)譜芯片中篩選出的靶標(biāo)基因。結(jié)論:NNMT促進(jìn)膠質(zhì)瘤增殖、侵襲的一個下游靶標(biāo)是GAP-43,其作用可能是通過甲基化調(diào)控實(shí)現(xiàn)的。
[Abstract]:Glioma is one of the most common malignant tumors in the central nervous system, which accounts for about 45 to 55%. of all brain tumors. The treatment of glioma mainly includes surgical treatment, radiation therapy and chemical therapy. However, the tumor is infiltrative growth, and there is no clear demarcation between the surrounding brain tissue and easy to relapse. The above traditional therapeutic measures are effective. New therapies such as gene therapy, such as gene therapy, are expected to be one of the ways to cure glioma, but there is still a lack of ideal and reliable target for treatment. Therefore, it has become a research field in the field of neuroscience to find a molecular target to regulate the malignant biological behavior of glioma cells and to clarify its pathological mechanism in the pathogenesis of glioma. Nicotinamide N- methyltransferase NNMT is a S- adenosine based -L- methionine dependent cytoplasmic enzyme that catalyzes the N- methyl unit of nicotinamide and other pyrimidine, forming a pyridine ion.NNMT in the liver tissue, while in the kidneys, lungs, skeletal muscles, placenta, heart and so on, low expression in the brain tissue or in the brain tissue is low. NNMT has been found to be abnormal in a variety of tumor tissues, including gastric adenocarcinoma, papillary thyroid carcinoma, colon cancer, hepatocellular carcinoma, lung cancer, pancreatic cancer, and so on. In non tumor lesions, NNMT is found in chronic obstructive pulmonary disease (COPD), atherosclerotic atherosclerosis, and the abnormal expression of.NNMT in the tumor in Parkinson's disease. Thanks, methylation, oxidative stress reactions are believed to play an important role in the development and development of tumor, but its specific mechanism is not clear about.Kristian Ovaska and other genetic changes that are closely related to GBM proliferation, survival and polymorphisms through the integration of large data frame integration technology Anduril, integration of large-scale molecular and clinical data. The NNMT gene is one of them. It is preliminarily found that down regulation of NNMT in vitro can significantly inhibit the proliferation of GBM, suggesting that NNMT may play an important role in the malignant biological behavior of glioma, but the specific mechanism is not yet studied. We will systematically study the role of NNMT in glioma from the following aspects: preparation The expression level of NNMT in different levels of glioma was detected by Western blot. The relationship between the expression of NNMT and the relationship between the expression of NNMT and the survival time of the patients was observed. Then, the cytological test was carried out in vitro, and the expression of NNMT in the lentivirus glioma cell line was detected. The effects of cell proliferation, migration, invasion, apoptosis and other cell malignancies on glioma cells were influenced by the study on the effects of NNMT on the dry character of glioma. Subsequently, differential gene expression spectrum chips were used to detect and screen the downstream target genes of the NNMT gene. As NNMT is the methylation regulator, we will also carry out methylation detection and clarify NNM T methylation targets the target. Finally, a preliminary study of the way NNMT regulates the downstream target is made to clarify the role of NNMT in promoting the proliferation and invasion of glioma. This experiment will be divided into four parts: the expression and clinical significance of 1.NNMT in human glioma; 2.NNMT on the proliferation, invasion, apoptosis and other cell functions of glioma. Sound; 3.NNMT's downstream target screening and validation in glioma; whether 4.NNMT can promote glioma proliferation and invasion through epigenetic regulation. Part 1 NNMT expression in human glioma and its clinical significance: To explore the expression and clinical meaning of NNMT in glioma: 59 cases of surgical resection of glioma The tumor specimens were made by tissue microarray, the expression of NNMT in different grade gliomas was detected by immunohistochemistry, and the follow-up data of the patients were analyzed. The relationship between the expression of NNMT in different grade gliomas and the survival time was analyzed, and the survival curve was made. Results: NNMT was overexpressed in glioma, and its table was associated with the disease. The increase in rational level was negatively related to the survival time of the patients with glioma, and the time of survival was shortened in patients with high NNMT expression. Conclusion: NNMT was overexpressed in human glioma, the level of expression was positively related to the malignant degree of glioma, and it was negatively related to the survival time. NNMT was associated with the malignant behavior of glioma. Second part NNMT was the proliferation of glioma and invasion of glioma. Research objective: the effects of NNMT on proliferation, migration, invasion and apoptosis of glioma cell lines were studied in vitro: the construction of U87, U251 cell line by lentivirus transfection of SiRNA and U251 cell line, and a blank control group to screen the stability of the cell Cell strain.Western blot verified the effect of lentivirus knockout, cell proliferation was detected by WST1, cell migration was detected by scratch assay, cell invasion was detected by Transwell method, cell apoptosis was detected by flow cytometry, and the effect of NNMT on NNMT was detected. The results showed that the proliferation, migration, and invasion ability of U87 and U251 glioma cells were clear after the SiRNA transfected to NNMT. Conclusion: the expression of SiRNA knockout NNMT in U87, U251 glioma cells can inhibit the proliferation, migration, apoptosis and other malignant phenotype of glioma cells, and inhibit the ability to form the ball (dry), and promote the apoptosis of the tumor. The third part of NNMT is screened in the downstream target of glioma and Objective: to screen the downstream target genes of NNMT to promote glioma cell proliferation, invasion and other malignant biological behavior. Research contents: two groups of SiRNA knockout U251 cell lines (U251-KD1, U251-KD2) were constructed with lentivirus transfection, and a blank control group was set up to screen the stable cell lines. The selected genes were analyzed, the genes of interest gene.PCR and Western Blot were selected to verify the target genes. Results: U251-KD1 and U251-KD2 two NNMT knockout cell lines were compared with U251-NC, and the gene expression spectrum chip analysis was carried out to select 61 down regulated genes and 32 upper genes, and to further analyze 8 of the interest. Down regulated genes MMP2, MMP7, RSP03, SEMA3F, TNFRSF19, ANXA8, APOBEC3G, CXCR7, these 8 genes are closely related to the proliferation and invasion of the tumor. At the same time, 5 up-regulated genes, PAK3, GAP43, ELAVL2, NEGR1, have been selected, and these five genes have different ways of inhibiting cancer. The results were consistent. Conclusion: the downstream target genes of NNMT in U251 glioma cells are up regulation of target genes MMP2, MMP7, RSP03, SEMA3F, TNFRSF19, ANXA8, APOBEC3G, CXCR7, etc., which are mainly related to proliferation, invasion and migration. The downstream target is mainly related to PAK3, GAP43, metastasis and cancer suppression. The fourth part is whether epigenetic regulation is promoted. Study on the proliferation and invasion of glioma: whether NNMT can promote the proliferation, invasion and apoptosis of glioma by regulating GAP-43. Research contents: two groups (U251-KD1, U251-KD2) of SiRNA knockout NNMT U251 cell line were constructed by lentivirus transfection, and a blank control group was set up to screen the stable cell line. The downstream action target was screened by methylation chip. The selected genes were studied, and the genes of interest were selected. Results: the lentivirus transfected to SiRNA NNMT U251 cell line two (U251-KD1, U251-KD2), resulting in the change of multiple methylation sites in GAP-43, GAP-43 is the target gene we screened in the gene expression chip. Conclusion: NNMT promotes the proliferation and invasion of glioma. A downstream target is GAP-43, which may be regulated by methylation.
【學(xué)位授予單位】：第二軍醫(yī)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R739.41

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