本文選題：HMGB1 + U87-MG細(xì)胞系　； 參考：《鄭州大學(xué)》2017年碩士論文

【摘要】：研究背景和目的:高遷移率族蛋白1(high mobility group box 1,HMGB1)是存在于真核生物細(xì)胞內(nèi)的一類非組蛋白染色體結(jié)合蛋白,參與基因轉(zhuǎn)錄、DNA修復(fù)、V(D)J重組、細(xì)胞外信號(hào)轉(zhuǎn)導(dǎo)、核小體的構(gòu)建、細(xì)胞的增殖、分化、遷移及凋亡,腫瘤的發(fā)生、生長(zhǎng)、轉(zhuǎn)移和浸潤(rùn)等。HMGB1含有215個(gè)氨基酸殘基,高度保守。HMGB1由三個(gè)不同的結(jié)構(gòu)域組成:兩個(gè)HMG box結(jié)構(gòu)域以及一個(gè)由30個(gè)氨基酸組成的C末端。HMGB1能與DNA結(jié)合,通過調(diào)節(jié)染色質(zhì)架構(gòu)(染色體中由非組蛋白構(gòu)成的結(jié)構(gòu)支架)進(jìn)而調(diào)控翻譯、修復(fù)和重組。在細(xì)胞受到刺激、細(xì)胞死亡、凋亡,組織缺氧及缺血再灌注時(shí),HMGB1可以被釋放到細(xì)胞外,參與炎癥、細(xì)胞遷移、分化和血管發(fā)生。許多研究顯示:HMGB1可參與腫瘤的發(fā)生和發(fā)展,其可能的機(jī)制包括HMGB1的高表達(dá)引起某些基因表達(dá)失調(diào),從而導(dǎo)致細(xì)胞具有腫瘤表型;此外,HMGB1的高表達(dá)還可使獲得腫瘤表型的細(xì)胞免于凋亡,最終導(dǎo)致腫瘤的發(fā)生。在結(jié)腸癌、前列腺癌、肺癌及食道癌等多種腫瘤組織中均發(fā)現(xiàn)了HMGB1的高表達(dá),同時(shí)也伴隨有晚期糖基化終末產(chǎn)物受體(receptor for advanced glycation end products,RAGE)的表達(dá)。RAGE是HMGB1的受體,通過JAK/STAT信號(hào)轉(zhuǎn)導(dǎo)通路對(duì)HMGB1的表達(dá)產(chǎn)生調(diào)節(jié)效應(yīng)。膠質(zhì)母細(xì)胞瘤(Glioblastoma,GBM)是顱內(nèi)最常見的惡性腫瘤,具有很高的致死率,其主要原因是由于腫瘤細(xì)胞的高浸潤(rùn)性和轉(zhuǎn)移性。根據(jù)世界衛(wèi)生組織(World Health Organization,WHO)所定標(biāo)準(zhǔn),膠質(zhì)瘤的病理分型可分為四級(jí):I級(jí)是毛細(xì)胞型星形細(xì)胞瘤、II級(jí)是彌漫性星形細(xì)胞瘤、III級(jí)為間變型星形細(xì)胞瘤、IV級(jí)為多形性GBM,其中I級(jí)和II級(jí)為低級(jí)別,屬良性腫瘤,III級(jí)和IV級(jí)為高級(jí)別,屬惡性腫瘤。近些年來(lái),針對(duì)膠質(zhì)瘤的治療雖然在手術(shù)、放化療方面取得了很大進(jìn)步,但由于腫瘤細(xì)胞的侵襲性、血腦屏障的不通透性以及對(duì)腫瘤細(xì)胞來(lái)源和其生長(zhǎng)機(jī)制的不明確性,大大局限了治療的有效性。有研究通過檢測(cè)人腦膠質(zhì)瘤組織中HMGB1基因的表達(dá)水平,探討其與膠質(zhì)瘤發(fā)生發(fā)展的關(guān)系,結(jié)果顯示:HMGB1 m RNA的表達(dá)水平在膠質(zhì)瘤組明顯高于對(duì)照組,但在低級(jí)別組與高級(jí)別組中的表達(dá)水平無(wú)顯著差異。也有研究顯示:高表達(dá)HMGB1的腫瘤細(xì)胞或者壞死的腫瘤細(xì)胞可將HMGB1釋放到細(xì)胞外,促使周圍腫瘤細(xì)胞的增殖,同時(shí)誘導(dǎo)小血管的再生,從而促使腫瘤的不斷生長(zhǎng);給予HMGB1或RAGE抑制劑,可抑制腫瘤細(xì)胞的增殖。目前對(duì)于HMGB1在人膠質(zhì)瘤組織中的表達(dá)與定位及其作用尚不完全清楚,如:HMGB1在各級(jí)膠質(zhì)瘤中的表達(dá)程度是否相同;表達(dá)在胞核還是胞漿;表達(dá)在何種類型細(xì)胞中;HMGB1是否影響膠質(zhì)瘤細(xì)胞的增殖、存活、凋亡和自噬,以及具體的機(jī)制是什么等問題尚待解決。因此,本課題的研究目的是闡明HMGB1在各級(jí)膠質(zhì)瘤組織中的表達(dá)程度,細(xì)胞定位與表達(dá)的細(xì)胞類型,初步探討HMBG1對(duì)膠質(zhì)瘤細(xì)胞線粒體的形態(tài)、細(xì)胞的凋亡與自噬的影響,為膠質(zhì)瘤的臨床治療提供理論依據(jù)。研究材料:選自中國(guó)人民解放軍第153中心醫(yī)院病理科提供的各級(jí)膠質(zhì)瘤組織的石蠟標(biāo)本,這些標(biāo)本均來(lái)自該院神經(jīng)外科膠質(zhì)瘤患者手術(shù)切除的組織,其中低級(jí)別標(biāo)本(I~Ⅱ)12例,高級(jí)別標(biāo)本(Ⅲ~Ⅳ)15例。細(xì)胞實(shí)驗(yàn)所用到的細(xì)胞系為U87-MG膠質(zhì)瘤細(xì)胞系,購(gòu)置于中國(guó)科學(xué)院細(xì)胞庫(kù)。研究方法:1.免疫組化單標(biāo)記或雙標(biāo)記染色,觀察HMGB1在各級(jí)別膠質(zhì)瘤中的表達(dá)程度、細(xì)胞定位及表達(dá)的細(xì)胞類型。2.質(zhì)粒的構(gòu)建及抽提:通過上海生工生物公司合成過表達(dá)HMGB1的質(zhì)粒,HMGB1連接在p EGFP-C1載體上(HMGB1與EGFP融合表達(dá)),對(duì)照載體是p EGFP-C1空載體。使用BIOMIGA無(wú)內(nèi)毒質(zhì)粒DNA小量提取試劑盒抽提質(zhì)粒。3.質(zhì)粒轉(zhuǎn)染:應(yīng)用Simple-Fect Transfection Reagent轉(zhuǎn)染試劑盒將過表達(dá)HMGB1的質(zhì)粒和空對(duì)照質(zhì)粒轉(zhuǎn)染U87-MG細(xì)胞,1)提取細(xì)胞蛋白,進(jìn)行Western Blotting(WB)實(shí)驗(yàn),觀察構(gòu)建的質(zhì)粒能否過表達(dá)HMGB1;2)用細(xì)胞免疫熒光法觀察過表達(dá)HMGB1是否影響線粒體的形態(tài)、細(xì)胞的凋亡或自噬。4.用促炎因子LPSIFN-γ聯(lián)合刺激U87-MG細(xì)胞,提取蛋白,進(jìn)行WB實(shí)驗(yàn),檢測(cè)炎癥是否影響HMGB1的表達(dá)。5.統(tǒng)計(jì)學(xué)分析:數(shù)據(jù)采用SPSS17.0或Origin70軟件分析,具體分析方法為卡方檢驗(yàn)以及單因素方差分析(One-Way ANOVA),數(shù)據(jù)采用均數(shù)±標(biāo)準(zhǔn)誤(Mean±SE)表示。結(jié)果:1.高級(jí)別膠質(zhì)瘤標(biāo)本中,HMGB1高表達(dá)的標(biāo)本比例顯著高于低級(jí)別標(biāo)本中的高表達(dá)比例(χ2=7.56,P=0.01);對(duì)于HMGB1中等程度表達(dá)的標(biāo)本比例(χ2=1.17,P=0.18)以及低表達(dá)的標(biāo)本比例(χ2=1.93,P=0.13),兩個(gè)級(jí)別間未出現(xiàn)顯著差異。2.HMGB1的陽(yáng)性信號(hào)主要定位在胞核,偶見在一些細(xì)胞的胞漿中也有HMGB1的陽(yáng)性信號(hào)。在低級(jí)別和高級(jí)別組織中,HMGB1在胞核中表達(dá)的細(xì)胞比例均顯著高于在胞漿中表達(dá)的細(xì)胞比例(低級(jí)別P=0.00797;高級(jí)別P=0.00130);而將低級(jí)別和高級(jí)別在胞核與胞漿的相應(yīng)數(shù)據(jù)進(jìn)行對(duì)比,均未檢測(cè)到有顯著差異(胞核P=0.79254;胞漿P=0.44251)。此外,隨著膠質(zhì)瘤級(jí)別的增加,HMGB1的表達(dá)出現(xiàn)不規(guī)則形態(tài)或分頁(yè)形態(tài),而在低級(jí)別膠質(zhì)瘤組織中,HMGB1的表達(dá)為均勻的圓形或橢圓形。3.各級(jí)膠質(zhì)瘤組織中,在膠質(zhì)瘤相關(guān)星形膠質(zhì)細(xì)胞(GFAP標(biāo)記)、膠質(zhì)瘤相關(guān)干細(xì)胞(Nestin標(biāo)記)、小膠質(zhì)細(xì)胞(Iba1標(biāo)記)、血管內(nèi)皮樣細(xì)胞以及神經(jīng)元樣細(xì)胞中均有HMGB1的陽(yáng)性表達(dá)。4.高級(jí)別膠質(zhì)瘤中先天免疫細(xì)胞小膠質(zhì)細(xì)胞表現(xiàn)出明顯的活化狀態(tài)(突起回縮,胞體增大和變圓),此外,炎性因子IL-6的表達(dá)明顯增加(P=0.0178)。采用促炎因子LPS和IFN-γ聯(lián)合刺激U87-MG細(xì)胞,HMGB1的蛋白表達(dá)量增加。5.HMGB1在U87-MG中,主要表達(dá)在胞核,核仁分布更為明顯。6.HMGB1過表達(dá)導(dǎo)致U87-MG細(xì)胞中線粒體發(fā)生斷裂;未發(fā)現(xiàn)HMGB1過表達(dá)對(duì)LC3B以及Caspase3表達(dá)的影響。結(jié)論:1.隨著膠質(zhì)瘤級(jí)別的增加,HMGB1的表達(dá)增加;HMGB1主要表達(dá)在胞核,并且隨著級(jí)別增加,HMGB1出現(xiàn)多形性分布;HMGB1在膠質(zhì)細(xì)胞、免疫細(xì)胞、腫瘤干細(xì)胞、血管樣細(xì)胞以及神經(jīng)元樣細(xì)胞中均有表達(dá)。2.在膠質(zhì)瘤細(xì)胞中,HMGB1在炎癥刺激下表達(dá)增加;HMGB1主要定位在胞核中,有較明顯的核仁定位。過表達(dá)HMGB1導(dǎo)致膠質(zhì)瘤細(xì)胞線粒體斷裂。
[Abstract]:Background and purpose: high mobility group protein 1 (high mobility group box 1, HMGB1) is a kind of non histone binding protein that exists in eukaryotic cells, participates in gene transcription, DNA repair, V (D) J recombination, extracellular signal transduction, nucleosome construction, cell proliferation, differentiation, migration and apoptosis, tumor occurrence, and growth. Metastasis and infiltration of.HMGB1 contain 215 amino acid residues, and highly conserved.HMGB1 consists of three different domains: two HMG box domains and a C terminal.HMGB1 composed of 30 amino acids can be combined with DNA to regulate translation, repair and repair by regulating the chromatin structure (the structural scaffold made up of non egg white in chromosomes). Recombinant. When cells are stimulated, cell death, apoptosis, tissue hypoxia and ischemia-reperfusion, HMGB1 can be released to the extracellular, involved in inflammation, cell migration, differentiation and angiogenesis. Many studies show that HMGB1 may participate in the occurrence and development of tumor, and its possible mechanism, including the high expression of HMGB1, causes some gene expression maladjustment, from In addition, the high expression of HMGB1 also makes the cells that obtain the tumor phenotype free from apoptosis and eventually lead to the occurrence of tumor. The high expression of HMGB1 is found in many tumor tissues such as colon, prostate, lung and esophagus cancer, and also with the advanced glycosylated end product receptor (receptor for a). The expression of dvanced glycation end products, RAGE) is the receptor of HMGB1, which regulates the expression of HMGB1 through the JAK/STAT signal transduction pathway. Glioblastoma (Glioblastoma, GBM) is the most common malignant tumor in the brain and has a high mortality rate. The main reason is the high invasion and metastasis of the tumor cells. According to the standards set by the WHO (World Health Organization, WHO), the pathological classification of glioma can be divided into four stages: I grade is hairy astrocytoma, II grade is diffuse astrocytoma, III is an astrocytoma, IV level is polymorphic, and I and II are low grade, benign tumor, III class and grade are advanced. In recent years, the treatment of glioma has made great progress in surgery and radiotherapy and chemotherapy, but the effectiveness of the treatment is limited by the invasiveness of the tumor cells, the inability of the blood brain barrier and the unknown origin of the tumor cells and the mechanism of its growth. The expression level of HMGB1 gene in the tumor tissue and the relationship with the development of glioma showed that the expression level of HMGB1 m RNA was significantly higher in the glioma group than in the control group, but there was no significant difference between the low level group and the advanced group. There were also studies showing that the tumor cells with high expression of HMGB1 or the tumor necrosis of the tumor were fine. The cell can release HMGB1 to the extracellular, promote the proliferation of peripheral tumor cells, induce the regeneration of small blood vessels, and induce the growth of the tumor. HMGB1 or RAGE inhibitors can inhibit the proliferation of tumor cells. At present, the expression and location and role of HMGB1 in human glioma tissues are not completely clear, such as: HMGB1 at all levels Whether the expression of glioma is the same, expressed in the nucleus or cytoplasm, and in what type of cells, whether HMGB1 affects the proliferation, survival, apoptosis and autophagy of glioma cells, and what the specific mechanism is still to be solved. Therefore, the purpose of this study is to clarify the expression of HMGB1 in glioma tissues at all levels. Degree, cell location and expression of cell types, preliminary study on the morphology of mitochondria, apoptosis and autophagy of glioma cells by HMBG1, and provide theoretical basis for the clinical treatment of glioma. Research materials: the paraffin specimens from the glioma tissues at all levels from the 153rd Central Hospital of the PLA Hospital, which are provided by the pathology department of the Chinese people's Liberation Army. All the specimens were from the surgical excision tissue of patients with glioma in the Department of Neurosurgery, of which 12 cases were low grade (I~ II) and 15 cases of high grade specimens (III ~ IV). The cell line used in the cell experiment was U87-MG glioma cell line and was purchased in the cell bank of the Chinese Academy of Sciences. Method: 1. immuno histochemical single marker or double marker staining were used to observe the HMGB1 in the cell line. The expression level of glioma at all levels, the construction and extraction of cell type.2. plasmids of cell location and expression: through the synthesis of HMGB1 plasmid in Shanghai biotech company, HMGB1 is connected to P EGFP-C1 vector (HMGB1 and EGFP fusion expression), and the control carrier is p EGFP-C1 empty carrier. DNA small quantity extraction of BIOMIGA non endotoxin plasmid is used. The plasmid transfection of plasmid.3. plasmid: transfection kit with Simple-Fect Transfection Reagent transfection kit transfected HMGB1 plasmid and empty control plasmid into U87-MG cells, 1) extract cell protein, carry out Western Blotting (WB) experiment, observe whether the constructed plasmid can reach HMGB1; 2) observe the HMGB1 expression by cell immunofluorescence. Whether the morphology of mitochondria, apoptosis of cells or autophagic.4. using pro-inflammatory factor LPSIFN- gamma to stimulate U87-MG cells, extract protein, and carry out WB test, detect whether inflammation affects HMGB1 expression.5. statistical analysis: the data are analyzed by SPSS17.0 or Origin70 software, the specific analysis method is chi square test and single factor ANOVA analysis (One-W) Ay ANOVA), the data were expressed with mean + standard error (Mean + SE). Results: in 1. high grade glioma specimens, the ratio of high expression of HMGB1 was significantly higher than that in low grade specimens (x 2=7.56, P=0.01); the proportion of specimens expressed in moderate HMGB1 (chi 2=1.17, P=0.18) and the proportion of low expressed specimens (chi 2=1.93, P=0.13), The positive signals that did not show significant difference between the two levels were mainly located in the nucleus, and the positive signals of HMGB1 were also found in the cytoplasm of some cells. In the low and high level tissues, the proportion of cells expressed in the nucleus of HMGB1 was significantly higher than that expressed in the cytoplasm (low grade P=0.00797; advanced P=0.00130). Compared with the corresponding data of the nucleus and cytoplasm of the nucleus, there were no significant differences (nucleus P=0.79254; cytoplasm P=0.44251). In addition, the expression of HMGB1 appeared irregular or paging with the increase of glioma level, while in the low grade glioma tissue, the expression of HMGB1 was even round or round. In oval.3. glioma tissues, glioma related astrocytes (GFAP markers), glioma related stem cells (Nestin markers), microglia (Iba1 markers), vascular endothelial like cells and neuron like cells all have HMGB1 positive expression in.4. high grade glioma, and the innate microglia in the high grade glioma is obvious. In addition, the expression of inflammatory factor IL-6 increased significantly (P=0.0178). U87-MG cells were stimulated by the combination of proinflammatory LPS and IFN- gamma. The protein expression of HMGB1 increased in U87-MG, mainly in the nucleus, and the distribution of nucleolus was more obvious in the U87-MG cell line. The effect of HMGB1 overexpression on LC3B and Caspase3 expression was not found. Conclusion: 1. as the grade of glioma increased, the expression of HMGB1 increased; HMGB1 was mainly expressed in the nucleus, and as the grade increased, HMGB1 appeared polymorphic; HMGB1 in glial cells, immune cells, tumor stem cells, vascular like cells and neurons. The expression of.2. in glioma cells was expressed in the glioma cells, and the expression of HMGB1 increased under the stimulation of inflammation; HMGB1 was mainly located in the nucleus and had a distinct nucleolus location. The overexpression of HMGB1 led to the rupture of mitochondria in glioma cells.
【學(xué)位授予單位】：鄭州大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R739.41

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