本文選題：Metadherin + 上皮間質(zhì)轉(zhuǎn)化　； 參考：《山東大學(xué)》2016年博士論文

【摘要】：彌漫大B細(xì)胞淋巴瘤(Diffuse large B-cell lymphoma, DLBC L)是一組高度侵襲性的淋巴瘤,在成人非霍奇金淋巴瘤(non-Hodgkin lymphoma, NH L)中約占30-40%,是NHL中最常見的亞型。DLBCL可原發(fā)于淋巴結(jié)或結(jié)外組織器官,也可由慢性淋巴細(xì)胞白血病/小淋巴細(xì)胞淋巴瘤、邊緣區(qū)淋巴瘤和濾泡性淋巴瘤(follicular lymphoma, FL)等低度惡性淋巴瘤轉(zhuǎn)化而來。作為高度侵襲性的淋巴瘤,DLBCL在細(xì)胞遺傳學(xué)、分子生物學(xué)、組織形態(tài)學(xué)、臨床表現(xiàn)及預(yù)后等方面均存在很大的異質(zhì)性。盡管由美羅華聯(lián)合環(huán)磷酰胺、阿霉素、長春新堿和潑尼松(R-CHOP)的一線方案,顯著提高了DLBCL患者的治療效果,但仍有約40%的患者難治、復(fù)發(fā)導(dǎo)致死亡。因此,深入研究DLBCL的生物學(xué)異質(zhì)性和侵襲機(jī)制,對于開發(fā)特異性治療靶點(diǎn)、優(yōu)化一線治療方案的選擇、提高完全緩解率、改善患者預(yù)后具有重要意義。異黏蛋白(metadherin, MTDH)是近年來發(fā)現(xiàn)的一個新的癌基因,又稱為星狀細(xì)胞上調(diào)基因-1(Astrocyte elevated gene-1, AEG-1)。最早是在研究人類免疫缺陷病毒(Human Immunodeficiency Virus-1, HIV-1)感染相關(guān)腦病時發(fā)現(xiàn)的新基因,命名為AEG-1。后來從侵襲性較高的乳腺癌細(xì)胞株中克隆出該蛋白,并且同時發(fā)現(xiàn)該蛋白能夠促進(jìn)乳腺癌細(xì)胞向肺部轉(zhuǎn)移,從而命名該蛋白為MTDH。人類的MTDH基因位于染色體8q22,基因全長3611bp,編碼產(chǎn)物是一種跨膜蛋白,包含582個氨基酸,分子量64KD。目前,已有大量的研究表明,MTDH在全身多種腫瘤中高表達(dá),如乳腺癌、黑色素瘤、肝癌、肺癌、前列腺癌、腎癌、結(jié)腸癌、神經(jīng)膠質(zhì)瘤、膽囊癌、卵巢癌、淋巴瘤等。且進(jìn)一步的研究證實(shí),MTDH能夠通過調(diào)節(jié)PI3K/AKT、NF-κB、Wnt/β-catenin等多個信號傳導(dǎo)通路及其相關(guān)基因的表達(dá)水平,來調(diào)控腫瘤的生長增殖、血管生成、侵襲轉(zhuǎn)移及耐藥等。同時,近年來發(fā)現(xiàn),上皮-間質(zhì)轉(zhuǎn)化(epithelial-mesenchymal transition, EMT)與腫瘤細(xì)胞的局部浸潤和遠(yuǎn)處轉(zhuǎn)移密切相關(guān)。EMT是指上皮細(xì)胞在特定生理或病理情況下向間質(zhì)細(xì)胞轉(zhuǎn)化,并伴隨明顯基因和表型改變的一個多階段過程。腫瘤細(xì)胞發(fā)生EMT時,細(xì)胞的形態(tài)、極性、遷移侵襲能力等形態(tài)學(xué)和生物學(xué)行為會出現(xiàn)變化,同時伴有上皮標(biāo)志物E-cadherin等表達(dá)減低和功能缺失,間質(zhì)細(xì)胞標(biāo)志物β-catenin、vimentin等過量表達(dá),以及某些轉(zhuǎn)錄因子Snail、Twist和ZEB1等表達(dá)和/或功能上調(diào)。在乳腺癌、肺癌、肝細(xì)胞癌、頭頸鱗癌、骨肉瘤、結(jié)腸癌及子宮頸癌等多種惡性腫瘤中已證實(shí),MTDH可以通過調(diào)節(jié)腫瘤細(xì)胞的EMT來促進(jìn)腫瘤的侵襲轉(zhuǎn)移。MTD H與EMT標(biāo)志物的表達(dá)和腫瘤分化、臨床分期、治療預(yù)后密切相關(guān)。MTDH促進(jìn)腫瘤細(xì)胞發(fā)生EMT,是通過調(diào)控多種信號通路來實(shí)現(xiàn)的,如：PI3K/AKT、Wnt/p-catenin、NF-κB和MAPK等信號通路,從而來調(diào)控腫瘤的侵襲性。其中Wnt/β-catenin是 MTDH發(fā)揮作用的一條重要信號通路,該通路在調(diào)控胚胎發(fā)育,維持成體組織細(xì)胞自我更新平衡中起重要作用,其異常激活與腫瘤的發(fā)生發(fā)展有關(guān)。該信號通路中的β-catenin在EMT和激活Wnt信號通路方面起到雙重作用。DLBCL為高度侵襲性淋巴瘤,易出現(xiàn)結(jié)外侵犯,DLBCL中是否存在EMT現(xiàn)象、MTDH與EMT在DLBCL侵襲性中的作用及調(diào)控機(jī)制如何,目前尚不清楚。本研究應(yīng)用免疫組織化學(xué)、細(xì)胞生物學(xué)及基因沉默等技術(shù),闡明了MTDH和EMT在DLBCL中的表達(dá)情況及二者的調(diào)控關(guān)系,探討了MTDH表達(dá)變化對DLBCL細(xì)胞侵襲性的影響和調(diào)控機(jī)制,為開發(fā)新的DLBCL分子標(biāo)志物和治療靶點(diǎn)提供了依據(jù)。第一部分MTDH和EMT標(biāo)志物在彌漫大B細(xì)胞淋巴瘤中的表達(dá)及臨床意義目的：DLBCL為高度侵襲性淋巴瘤,存在很大的異質(zhì)性,但對其侵襲機(jī)制的研究尚不清楚。MTDH是近年來發(fā)現(xiàn)的一個新的癌基因。大量研究表明,MTDH在全身多種腫瘤中高表達(dá),并通過調(diào)節(jié)PI3K/AKT、NF-κB、Wnt/β-catenin等多個信號傳導(dǎo)通路及其相關(guān)基因的表達(dá)水平,來調(diào)控腫瘤的生長增殖、血管生成、侵襲轉(zhuǎn)移及耐藥等。EMT與腫瘤細(xì)胞的局部浸潤和遠(yuǎn)處轉(zhuǎn)移密切相關(guān)。腫瘤細(xì)胞發(fā)生EMT時,其生物學(xué)行為和分子標(biāo)志物會出現(xiàn)改變。MTDH可以通過調(diào)節(jié)腫瘤細(xì)胞的EMT來促進(jìn)腫瘤的侵襲轉(zhuǎn)移。為了研究MTDH口EMT在DLBCL中的表達(dá)情況,我們以人DLBCL細(xì)胞株LY1和LY8為研究對象,首先采用蛋白印記分析技術(shù)檢測MTDH和EMT標(biāo)志物vimentin、ZEB1蛋白在DLBCL細(xì)胞株中的表達(dá)情況。并收集病理診斷明確的DLBCL和淋巴結(jié)反應(yīng)性增生的組織標(biāo)本,應(yīng)用免疫組織化學(xué)技術(shù)對MTDH在兩組織中的表達(dá)情況進(jìn)行檢測,并與患者的臨床資料進(jìn)行相關(guān)性分析,探討它們在DLBCL侵襲性中的作用。材料與方法：1.標(biāo)本收集和分離外周血單個核細(xì)胞2.LY1和LY8細(xì)胞株培養(yǎng)3.蛋白提取與蛋白印跡分析4.標(biāo)本和臨床病例資料收集5.免疫組織化學(xué)分析6.統(tǒng)計學(xué)分析結(jié)果：1. Western blot結(jié)果顯示,MTDH、vimentin和 ZEB1蛋白在DLBCL細(xì)胞株中均高表達(dá),而在對照正常人外周血單個核細(xì)胞中幾乎不表達(dá)。MTDH的目的條帶位于75kD處,vimentin的目的條帶位于54kD處,ZEB1的分子量最大,目的條帶位于124kD處。2.30例DLBC L組織標(biāo)本中只有1例評分為0,40.0%(12/30例)的DLBCL組織標(biāo)本中MTDH為低表達(dá),60.0%(18/30例)的DLBCL組織標(biāo)本中MTDH為高表達(dá),表達(dá)的MTDH染色多見于細(xì)胞漿,也可少量見于細(xì)胞核中。而MTDH在淋巴結(jié)反應(yīng)性增生組織中幾乎不表達(dá)。3. MTDH的表達(dá)與DLBCL患者臨床特征的相關(guān)性分析結(jié)果顯示,MTDH的高表達(dá)與DLBCL患者的年齡(P=0.458)、性別(P=0.284)、LDH (P=0.249)無相關(guān)性,而與臨床分期(P=0.04)、有B癥狀(P=0.004)、危險度分層(P=0.033)呈正相關(guān),P值均0.05,有統(tǒng)計學(xué)意義。結(jié)論：1.本研究通過Western blot技術(shù)的檢測,發(fā)現(xiàn)MTDH、vimentin和 ZEB1蛋白在DLBCL細(xì)胞株中均高表達(dá)。2.IHC結(jié)果顯示,60.0%(18/30例)的DLBCL組織中MTDH為高表達(dá),表達(dá)的MTDH多位于細(xì)胞漿中,少量見于細(xì)胞核中。3. MTDH的高表達(dá)與DLBCL患者的臨床分期、有B癥狀和危險度分層呈正相關(guān)。第二部分MTDH表達(dá)變化對彌漫大B細(xì)胞淋巴瘤侵襲性的影響及其調(diào)控機(jī)制目的：在多種惡性腫瘤中證實(shí),MTDH可以通過調(diào)節(jié)腫瘤細(xì)胞的EMT來促進(jìn)腫瘤的侵襲轉(zhuǎn)移。MTDH與EMT標(biāo)志物的表達(dá)和腫瘤分化、臨床分期、治療預(yù)后密切相關(guān)。MTDH是通過調(diào)控PI3K/AKT, NF-κB. Wnt/β-catenin和MAPK等多種信號通路來促進(jìn)腫瘤細(xì)胞EMT的發(fā)生,從而調(diào)控腫瘤的侵襲性。本研究以人DLBCL細(xì)胞株LY8為研究對象,應(yīng)用慢病毒載體介導(dǎo)的RNAi沉默MTDH基因,然后檢測EMT標(biāo)志物vimentin和ZEB1蛋白的表達(dá)變化和DLBCL細(xì)胞侵襲能力的改變。進(jìn)一步研究在DLBCL中是否存在EMT現(xiàn)象,以及MTDH表達(dá)變化對DLBCL細(xì)胞侵襲性的影響和調(diào)控機(jī)制。材料與方法：1.LY8細(xì)胞株培養(yǎng)2.慢病毒載體介導(dǎo)的RNAi靶向沉默LY8細(xì)胞株的MTDH基因3.流式細(xì)胞術(shù)檢測細(xì)胞轉(zhuǎn)染率4.蛋白提取及蛋白印跡分析5.侵襲小室實(shí)驗(yàn)6.統(tǒng)計學(xué)分析結(jié)果：1.慢病毒載體介導(dǎo)的MTDH RNAi可以抑制DLBCL細(xì)胞中MTDH的表達(dá)。2.應(yīng)用慢病毒顆粒沉默MTDH基因后,DLBCL細(xì)胞中Vimentin和ZEB1蛋白的表達(dá)水平明顯降低(P0.05)3. Transwell侵襲小室實(shí)驗(yàn)結(jié)果顯示,慢病毒載體介導(dǎo)的MTDH基因沉默可以降低DLBCL細(xì)胞株的遷移力和侵襲力(P0.05)。結(jié)論：1. DLBCL中存在類EMT現(xiàn)象。2. MTDH基因沉默可以降低EMT標(biāo)志物Vimentin 和 ZEB1蛋白在DLBCL細(xì)胞株中的表達(dá)。3.抑制MTDH的表達(dá)可以降低DLBCL細(xì)胞株的遷移力和侵襲力。4.MTDH可能是通過Wnt/β-catenin信號通路調(diào)節(jié)DLBCL的EMT。
[Abstract]:Diffuse large B cell lymphoma (Diffuse large B-cell lymphoma, DLBC L) is a highly invasive group of lymphoma, which accounts for 30-40% in adult non Hodgkin's lymphoma (non-Hodgkin lymphoma, NH L). It is the most common subtype in lymph node or extranodal organs, or chronic lymphocytic leukemia / lymphatic lymph nodes. Low degree malignant lymphoma such as cell lymphoma, marginal zone lymphoma and follicular lymphoma (follicular lymphoma, FL). As a highly invasive lymphoma, DLBCL has great heterogeneity in cytogenetics, molecular biology, histomorphology, clinical manifestation, and prognosis. The first-line scheme of amines, adriamycin, vincristine and prednisone (R-CHOP) significantly improves the therapeutic effect of DLBCL patients, but there are still about 40% of the patients' refractory and recurrent deaths. Therefore, the study of the biological heterogeneity and invasion mechanism of DLBCL, the development of specific therapeutic targets, the optimization of the selection of first-line treatment options, and the improvement of the complete delay. The rate of solution is important to improve the prognosis of patients. Metadherin (MTDH) is a new oncogene found in recent years, also known as -1 (Astrocyte elevated gene-1, AEG-1). It was first found in the study of human immunodeficiency virus (Human Immunodeficiency Virus-1, HIV-1) infection related encephalopathy. The new gene, named AEG-1., was later cloned from the aggressive breast cancer cell strain and found that the protein could promote the metastasis of breast cancer cells to the lungs, which named the MTDH gene of MTDH. human being on chromosome 8q22, the full 3611bp of the gene, and the encoding product of a transmembrane protein containing 582 ammonia. At present, basic acid, molecular weight 64KD., a large number of studies have shown that MTDH is highly expressed in various tumors of the whole body, such as breast cancer, melanoma, liver cancer, lung cancer, prostate cancer, kidney cancer, colon cancer, glioma, gallbladder cancer, ovarian cancer, lymphoma and so on. Further research has confirmed that MTDH can be used to regulate PI3K/AKT, NF- kappa B, Wnt/ beta -catenin and so on. The expression level of signal transduction pathway and its related genes to regulate tumor growth, angiogenesis, invasion and metastasis and resistance. Meanwhile, in recent years, epithelial-mesenchymal transition (EMT) is closely related to the local infiltration and distant metastasis of tumor cells..EMT refers to the epithelial cells in a specific life. Changes in morphological and biological behavior such as cell morphology, polarity, migration and invasion ability and other changes in cell morphology, polarity, migration and invasion, as well as epithelial markers such as E-cadherin expression reduction and functional deletion, and interstitial cells marked by EMT. The expression and / or function of some transcriptional factors, such as beta -catenin, vimentin, and some transcription factors, such as Snail, Twist and ZEB1, are up-regulated in many malignant tumors, such as breast cancer, lung cancer, hepatocellular carcinoma, head and neck squamous cell carcinoma, osteosarcoma, colon and cervical cancer, and MTDH can promote tumor invasion and metastasis by regulating the EMT of tumor cells. The expression of D H and the expression of EMT markers, tumor differentiation, clinical stage and treatment prognosis are closely related to.MTDH to promote EMT in tumor cells. It is realized by regulating a variety of signal pathways, such as PI3K/AKT, Wnt/p-catenin, NF- kappa B and MAPK, to regulate the invasiveness of the tumor. This pathway plays an important role in regulating embryo development and maintaining the self renewal balance of adult tissue cells. Its abnormal activation is related to the occurrence and development of tumor. The beta -catenin in this signal pathway plays a dual role in EMT and activation of Wnt signaling pathway,.DLBCL is highly invasive lymphoma and is prone to extranodal invasion. It is not clear whether there is a phenomenon of EMT in DLBCL, the role of MTDH and EMT in DLBCL invasiveness and its regulatory mechanism. This study uses immunohistochemistry, cell biology and gene silencing techniques to elucidate the expression of MTDH and EMT in DLBCL and the regulation relationship between the two and the MTDH expression changes to DLBCL cells. Invasive effects and regulatory mechanisms provide a basis for the development of new DLBCL markers and therapeutic targets. Part 1 the expression and clinical significance of MTDH and EMT markers in diffuse large B cell lymphoma: DLBCL is a highly invasive lymphoma with great heterogeneity, but the study of its invasion mechanism is not clear.MTD H is a new oncogene found in recent years. A large number of studies have shown that MTDH is highly expressed in many kinds of tumors and regulates the growth and proliferation of tumor, blood Guan Shengcheng, invasion and resistance and other.EMT and tumor cells by regulating the expression of multiple signal transduction pathways, such as PI3K/AKT, NF- kappa B, Wnt/ beta -catenin, and other related genes. Local invasion is closely related to distant metastasis. When the tumor cells occur EMT, the biological behavior and molecular markers will change.MTDH to promote the invasion and metastasis of the tumor by regulating the EMT of the tumor cells. In order to study the expression of MTDH mouth EMT in DLBCL, we take the human DLBCL cell strain LY1 and LY8 as the research object, first of all. The expression of MTDH and EMT markers vimentin, ZEB1 protein in DLBCL cell lines was detected with protein imprint analysis technique. The pathological diagnosis of DLBCL and lymphoid reactive hyperplasia tissue specimens were collected, and the expression of MTDH in two tissues was detected by immunohistochemistry and the clinical data of the patients were carried out. Correlation analysis, their role in DLBCL invasiveness. Materials and methods: 1. specimens collected and separated from peripheral blood mononuclear cells 2.LY1 and LY8 cell lines, 3. protein extraction and Western blot analysis 4. specimens and clinical case data collection 5. immunohistochemical analysis 6. statistical analysis results: 1. Western blot results showed that MTDH, vimentin and ZEB1 protein were highly expressed in DLBCL cell lines, but the target band of almost non expression.MTDH in peripheral blood mononuclear cells of normal human was located at 75kD. The target band of vimentin was located at 54kD, and the molecular weight of ZEB1 was the largest. The target band was located at 124kD.2.30 case of DLBC tissue specimens, only 1 cases were scored ( The expression of MTDH in DLBCL tissue specimens of 12/30 cases was low, and MTDH was highly expressed in DLBCL tissue specimens of 60% (18/30). The expression of MTDH staining was mostly found in cytoplasm and in the nucleus, but MTDH in the reactive hyperplasia tissues of lymph nodes almost did not express the correlation analysis between the expression of.3. MTDH and the clinical characteristics of DLBCL patients. The high expression of MTDH was not related to the age of DLBCL patients (P=0.458), sex (P=0.284) and LDH (P=0.249), but it was positively correlated with the clinical stage (P=0.04), B symptoms (P=0.004), risk stratification (P=0.033), and P values were 0.05, and there were statistical significance. The high expression of.2.IHC in DLBCL cell lines showed that MTDH was highly expressed in 60% (18/30) DLBCL tissues, and the MTDH expressed in the cytoplasm was mostly located in the cytoplasm. The high expression of.3. MTDH in the nucleus was in positive correlation with the clinical stages of DLBCL patients. There was a positive correlation between the B symptoms and risk stratification of B. The second part MTDH expression changed to diffuse large B. The influence and regulatory mechanism of cell lymphoma invasiveness: in a variety of malignant tumors, MTDH can promote tumor invasion and metastasis by regulating the EMT of tumor cells to transfer the expression of.MTDH and EMT markers and tumor differentiation. Clinical staging, the prognosis closely related to the prognosis of.MTDH is through the regulation of PI3K/AKT, NF- kappa B. Wnt/ beta -catenin and MAPK. A variety of signal pathways are used to promote the occurrence of tumor cell EMT and regulate tumor invasiveness. In this study, the human DLBCL cell line LY8 was used as the research object. The RNAi silencing MTDH gene mediated by the lentivirus vector was used to detect the changes in the expression of the EMT markers vimentin and ZEB1 protein and the change of the invasive ability of DLBCL cells. Whether there is EMT in DLBCL, and the effect of MTDH expression on the invasiveness of DLBCL cells and its regulatory mechanism. Materials and methods: 1.LY8 cell line culture 2. lentivirus vector mediated RNAi targeted silent LY8 cell line, MTDH gene 3. flow cytometry, cell transfection rate 4. protein extraction and Western blot analysis 5. invasive chamber experiment 6 The results of statistical analysis: 1. MTDH RNAi mediated by lentivirus vector can inhibit the expression of MTDH in DLBCL cells,.2. application of lentivirus particles silencing MTDH gene, the expression level of Vimentin and ZEB1 protein in DLBCL cells decreased significantly (P0.05) 3. Transwell invasive laboratory results showed that the lentivirus vector mediated MTDH gene silencing could To reduce the mobility and invasiveness of DLBCL cell lines (P0.05). Conclusion: the existence of EMT phenomenon.2. MTDH gene silencing in 1. DLBCL can reduce the expression of EMT markers Vimentin and ZEB1 protein in DLBCL cell lines. The signal pathway regulates the EMT. of DLBCL
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R733.1

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