【摘要】：B-Myb是高度保守的轉(zhuǎn)錄因子Myb家族的成員之一,在有增殖能力的細胞中普遍表達,并在細胞周期進程中起到重要作用。有研究發(fā)現(xiàn),B-Myb在很多癌癥細胞中高表達,如乳腺癌、肝細胞癌、神經(jīng)母細胞瘤等。這提示我們,B-Myb在癌癥的發(fā)生發(fā)展過程中可能發(fā)揮重要作用。迄今為止,B-Myb在肺癌中的表達及其作用機制尚不明確,故本論文主要研究B-Myb在肺癌組織樣本中的表達水平及其對肺癌細胞增殖、遷移侵襲、腫瘤形成的影響,并探究其分子機制。第一部分B-Myb過表達對肺癌細胞增殖、遷移侵襲及腫瘤形成的影響及機制研究目的:1.研究B-Myb在肺癌組織中表達與腫瘤的臨床病理特征之間的關系。2.檢測B-Myb過表達對肺癌細胞增殖、細胞周期、遷移侵襲、腫瘤形成的影響。3.初步闡明B-Myb過表達促進肺癌細胞增殖、遷移侵襲及腫瘤形成的分子機制。方法:1.采用q RT-PCR、western blot及IHC檢測肺癌組織和正常肺組織中B-Myb的表達水平,統(tǒng)計分析B-Myb在肺癌組織中表達與腫瘤的臨床病理特征之間的關系。2.采用慢病毒感染的方法將目的基因B-Myb轉(zhuǎn)染到肺癌細胞中,建立B-Myb過表達的細胞模型;q RT-PCR和western blot檢測B-Myb及靶基因的m RNA和蛋白的表達;CCK-8檢測細胞增殖;FCM檢測細胞周期;劃痕實驗和Transwell檢測細胞遷移侵襲;裸鼠成瘤實驗檢測肺癌細胞體內(nèi)成瘤能力。3.RNA-seq檢測肺癌細胞系H1299的B-Myb過表達組樣本與對照組樣本,GO富集分析和pathway富集分析篩選差異表達的基因及相關的信號通路。結果:1.檢測40例肺癌患者和7例對照正常肺組織c DNA芯片中B-Myb的m RNA表達水平,并通過IHC檢測69例肺癌患者及3例正常肺組織芯片中B-Myb的蛋白表達水平。統(tǒng)計分析顯示,肺癌組織中B-Myb的m RNA和蛋白表達水平均顯著高于正常肺組織,B-Myb的蛋白表達主要定位在細胞質(zhì)內(nèi),且B-Myb的表達量與腫瘤的大小、淋巴結轉(zhuǎn)移以及轉(zhuǎn)移癌等密切相關。進一步檢測肺癌6個細胞系H1299、A549、H157、H446、H524和H460中B-Myb的m RNA表達水平,結果發(fā)現(xiàn)在肺癌細胞H1299和A549中B-Myb的m RNA表達相對較低。2.肺癌細胞系H1299和A549的B-Myb過表達細胞模型成功建立,且過表達組較對照組的目的基因B-Myb表達量至少高出4倍;CCK-8結果顯示,B-Myb過表達促進肺癌細胞的增殖;FCM檢測結果顯示,B-Myb過表達組較對照組S期細胞數(shù)量顯著增加,且G1期細胞數(shù)量顯著減少;劃痕實驗和Transwell遷移實驗結果顯示,B-Myb過表達促進肺癌細胞遷移;Transwell侵襲結果顯示,B-Myb過表達促進肺癌細胞侵襲;體內(nèi)實驗結果顯示,B-Myb過表達促進肺癌細胞的腫瘤形成。3.RNA-seq的檢測和分析結果顯示,B-Myb過表達誘導390個基因的差異表達,其中表達上調(diào)的有300個基因,表達下調(diào)的有90個基因。GO富集分析結果顯示差異表達的基因功能主要與細胞外基質(zhì)、生長因子、細胞發(fā)育進程有關。pathway富集分析結果顯示主要的信號通路包括細胞粘附因子通路、PI3K-Akt信號通路、癌癥通路及Ras信號通路。我們對部分差異表達的基因CCNA1、COL11A1、COL6A1、FN1、MMP2、NID1、FLT4、SPARC、INSR、IDH2、PDK3和IGFBP3進行q RT-PCR檢測,差異表達的趨勢與RNA-seq數(shù)據(jù)分析結果一致。進一步western blot分析顯示,B-Myb過表達顯著提高ERK和Akt磷酸化水平,能夠激活ERK和Akt信號通路。結論:1.肺癌組織中B-Myb的m RNA水平和蛋白水平顯著高于正常肺組織,B-Myb的蛋白表達主要定位在細胞質(zhì)內(nèi),且B-Myb的表達量與腫瘤的大小、淋巴結轉(zhuǎn)移以及轉(zhuǎn)移癌等密切相關。2.體外實驗顯示,B-Myb過表達能夠促進細胞的增殖、細胞周期進程和遷移侵襲;體內(nèi)實驗顯示,B-Myb過表達能夠提高肺癌細胞的腫瘤形成能力。3.RNA-seq檢測分析結果顯示,差異表達的基因功能主要與細胞外基質(zhì)、生長因子、細胞發(fā)育進程有關,對部分差異表達的基因進行q RT-PCR檢測,差異表達的趨勢與RNA-seq數(shù)據(jù)分析結果一致,pathway富集分析結果顯示主要的信號通路包括細胞粘附因子通路、PI3K-Akt信號通路、癌癥通路及Ras信號通路。Western blot分析顯示,B-Myb過表達顯著提高ERK和Akt磷酸化水平,能夠激活ERK和Akt信號通路,B-Myb能夠促進肺癌的發(fā)生發(fā)展,或許部分是通過對ERK和Akt信號通路進行調(diào)節(jié)。第二部分B-Myb干擾對肺癌細胞增殖、遷移侵襲及腫瘤形成的影響及機制研究目的:1.檢測B-Myb干擾對肺癌細胞增殖、周期、遷移侵襲、腫瘤形成等功能的影響。2.初步闡明B-Myb干擾抑制肺癌細胞增殖、遷移侵襲及腫瘤形成的分子機制。方法:1.采用慢病毒感染和瞬時轉(zhuǎn)染的方法將目的基因B-Myb的干擾序列轉(zhuǎn)染到肺癌細胞中,建立B-Myb干擾的細胞模型;q RT-PCR和western blot檢測B-Myb及靶基因的m RNA和蛋白的表達;CCK-8檢測細胞增殖;FCM檢測細胞周期;劃痕和Transwell檢測細胞遷移侵襲;裸鼠成瘤檢測體內(nèi)成瘤能力。2.RNA-seq檢測H1299的B-Myb干擾組與對照組樣本,GO富集分析和pathway富集分析篩選出差異表達的基因及相關的信號通路。結果:1.肺癌細胞H1299和A549的B-Myb干擾模型成功建立,且B-Myb干擾效率大于60%;CCK-8結果顯示,B-Myb干擾抑制肺癌細胞的增殖;FCM檢測結果顯示,肺癌細胞B-Myb干擾后S期細胞數(shù)量減少,且G1期細胞數(shù)量顯著增加;劃痕和Transwell遷移結果顯示,B-Myb干擾抑制肺癌細胞遷移;Transwell侵襲結果顯示,B-Myb干擾抑制肺癌細胞侵襲;體內(nèi)實驗結果顯示,B-Myb干擾抑制肺癌細胞的腫瘤形成。2.RNA-seq的檢測和分析結果顯示,B-Myb干擾誘導13362個基因差異表達,其中包括6343個基因表達上調(diào),7019個基因表達下調(diào)。GO富集分析顯示差異表達的基因主要參與調(diào)控細胞信號轉(zhuǎn)導、細胞周期、細胞增殖、細胞凋亡及遷移侵襲等功能,Pathway富集分析的主要是MAPK信號通路、凋亡和細胞周期相關信號通路。我們對部分差異表達的基因COL11A1、FLT4、SPARC、IDH2、PDK3和IGFBP3進行q RT-PCR檢測,差異表達的趨勢與RNA-seq數(shù)據(jù)分析結果一致。結論:1.體外實驗顯示,B-Myb干擾能夠抑制肺癌細胞的增殖、遷移侵襲、且S期細胞減少;體內(nèi)實驗顯示,B-Myb干擾能夠降低肺癌細胞的腫瘤形成能力。2.RNA-seq檢測并分析顯示,細胞外基質(zhì)、生長因子、細胞發(fā)育進程都存在基因表達的不同程度的下調(diào)。對部分差異表達的基因進行q RT-PCR檢測,差異表達的趨勢與RNA-seq數(shù)據(jù)分析結果一致,pathway富集分析結果顯示,主要的信號通路包括MAPK信號通路、凋亡和細胞周期相關信號通路。
[Abstract]:B-Myb is a member of the highly conserved transcription factor Myb family and is widely expressed in proliferating cells and plays an important role in the process of cell cycle. Some studies have found that B-Myb is highly expressed in many cancer cells, such as breast cancer, hepatocellular carcinoma, and neuroblastoma. This suggests that B-Myb is in the development of cancer. So far, the expression and mechanism of B-Myb in lung cancer are not clear. Therefore, this paper mainly studies the expression level of B-Myb in lung cancer tissue samples and its effect on lung cancer cell proliferation, migration and invasion, tumor formation, and explore its molecular mechanism. The first part of B-Myb overexpression on lung cancer The effect and mechanism of cell proliferation, migration, invasion and tumor formation: 1. study the relationship between the expression of B-Myb in lung cancer tissue and the clinicopathological features of tumor.2. detection of B-Myb overexpression on the proliferation, cell cycle, migration and invasion, and the effect of.3. on the proliferation of lung cancer cells and promoting the proliferation of lung cancer cells, migration and migration of lung cancer cells The molecular mechanism of invasion and tumor formation. Methods: 1. the expression of B-Myb in lung cancer tissues and normal lung tissues was detected by Q RT-PCR, Western blot and IHC. The relationship between the expression of B-Myb in lung cancer tissues and the clinicopathological features of the tumor was statistically analyzed.2. using the lentivirus infection method to transfect the target gene B-Myb to lung cancer. In the cell, B-Myb overexpressed cell model was established; Q RT-PCR and Western blot were used to detect the expression of M RNA and protein of B-Myb and target genes; CCK-8 detection of cell proliferation; FCM detection of cell cycle; scratch test and Transwell detection of cell migration and invasion; nude mice tumor testing detection of lung cancer cells in vivo tumorigenicity.3.RNA-seq detection of lung cancer cell lines 99 B-Myb overexpressed group samples and control group samples, GO enrichment analysis and pathway enrichment analysis were used to screen differentially expressed genes and related signaling pathways. Results: 1. detection of M RNA expression level of B-Myb in 40 cases of lung cancer patients and 7 normal lung tissue C DNA chips, and 69 cases of lung cancer and 3 normal lung tissue chips by IHC The protein expression level of middle B-Myb showed that the expression level of M RNA and protein of B-Myb in lung cancer tissues was significantly higher than that of normal lung tissue. The protein expression of B-Myb was mainly located in the cytoplasm, and the expression of B-Myb was closely related to the size of tumor, lymph node metastasis and metastatic carcinoma. Further detection of the 6 cell line of lung cancer H12 99, A549, H157, H446, H524 and H460 B-Myb m RNA expression level. The results showed that B-Myb M protein expression in lung cancer cells H1299 and A549 was relatively low, and the overexpressed cell model was successfully established, and the overexpressed group was at least 4 times higher than the control group. The expression of overexpression promoted the proliferation of lung cancer cells, and the results of FCM detection showed that the number of S phase cells in the B-Myb overexpression group was significantly increased and the number of G1 cells decreased significantly. The results of scratch test and Transwell migration showed that B-Myb overexpression promoted the migration of lung cancer cells; the result of Transwell invasion showed that the over expression of B-Myb promoted lung cancer cells. The results of the in vivo experiment showed that B-Myb overexpression promoted the tumor formation of.3.RNA-seq in lung cancer cells. The results showed that B-Myb overexpression induced the differential expression of 390 genes, of which 300 genes were up-regulated, and 90 gene.GO enrichment analysis showed that the function of differentially expressed genes was mainly related to the expression of down regulation. The results of extracellular matrix, growth factor, and cell development related to.Pathway enrichment analysis showed that the main signaling pathways included cell adhesion factor pathway, PI3K-Akt signaling pathway, cancer pathway and Ras signaling pathway. We expressed genes CCNA1, COL11A1, COL6A1, FN1, MMP2, NID1, FLT4, SPARC, INSR, INSR, INSR, INSR, SPARC, and CCNA1 The trend of differential expression was consistent with the results of RNA-seq data analysis. Further western blot analysis showed that B-Myb overexpression significantly increased the level of phosphorylation of ERK and Akt, and could activate ERK and Akt signaling pathways. Conclusion: 1. the B-Myb M levels and protein levels in lung cancer tissues are significantly higher than those of normal lung tissues. The protein expression of 1. lung cancer tissues is significantly higher than that of normal lung tissue. It is mainly located in the cytoplasm, and the expression of B-Myb is closely related to the size of tumor, lymph node metastasis and metastatic carcinoma. In vitro,.2. experiments show that overexpression of B-Myb can promote cell proliferation, cell cycle process and migration invasion. In vivo experiments show that B-Myb overexpression can improve the tumor formation ability of lung cancer cells.3.RNA-seq The results of detection analysis showed that the differentially expressed gene functions were mainly related to extracellular matrix, growth factor, cell development process, and Q RT-PCR detection for some differentially expressed genes. The trend of differential expression was consistent with the results of RNA-seq data analysis. Pathway enrichment analysis showed that the main signal pathways included cell adhesion factors. The pathway, PI3K-Akt signaling pathway, cancer pathway and Ras signaling pathway.Western blot analysis showed that B-Myb overexpression significantly increased the level of ERK and Akt phosphorylation, activated ERK and Akt signaling pathways, and B-Myb could promote the development of lung cancer, perhaps partly through the regulation of ERK and Akt signaling pathways. The second part interferes with lung cancer. Effects and mechanisms of cell proliferation, migration and invasion and tumor formation: 1. detection of the effects of B-Myb interference on proliferation, cycle, migration and invasion, and tumor formation of lung cancer cells..2. preliminarily clarifies the molecular mechanism of B-Myb interference to inhibit the proliferation, migration and invasion of lung cancer cells and the formation of tumor. Methods 1. use lentivirus infection and transient transformation. The staining method transfected the interference sequence of the target gene B-Myb into the lung cancer cells and established the B-Myb interference cell model; Q RT-PCR and Western blot detected the B-Myb and the expression of M RNA and protein of the target gene; CCK-8 detection of cell proliferation; FCM detection of cell cycle; scratch and Transwell detection of cell migration and invasion; tumor formation detection in nude mice. .2.RNA-seq detection of H1299 B-Myb interference group and control group samples, GO enrichment analysis and pathway enrichment analysis screened differentially expressed genes and related signaling pathways. Results: 1. the B-Myb interference model of H1299 and A549 in lung cancer cells was successfully established, and B-Myb interference efficiency was more than 60%; CCK-8 results showed that B-Myb interference inhibited lung cancer cells. The results of FCM detection showed that the number of S cells decreased and the number of G1 cells increased significantly after B-Myb interference, and the results of scratch and Transwell migration showed that B-Myb interference inhibited the migration of lung cancer cells; the results of Transwell invasion showed that B-Myb interference inhibited the invasion of lung cancer cells; in vivo experimental results showed that B-Myb interference inhibited lung cancer. The detection and analysis of the tumor formation of.2.RNA-seq showed that B-Myb interference induced 13362 differentially expressed genes, including 6343 gene expression up-regulated, 7019 gene expression down-regulation.GO enrichment analysis showed that the differentially expressed genes were mainly involved in regulating cell signal transduction, cell cycle, cell proliferation, cell apoptosis and migration invasion. MAPK signaling pathway, apoptosis and cell cycle related signal pathways were mainly analyzed by Pathway enrichment analysis. We detected Q RT-PCR in some differentially expressed genes COL11A1, FLT4, SPARC, IDH2, PDK3 and IGFBP3. The trend of differential expression was consistent with that of RNA-seq data analysis. Conclusion: 1. in vitro experiments showed that B-Myb interference could be suppressed. The proliferation, migration and invasion of lung cancer cells and the decrease of S phase cells; in vivo experiments showed that B-Myb interference could reduce the tumor formation ability of lung cancer cells by.2.RNA-seq detection and analysis showed that extracellular matrix, growth factor, and cell development process were all down regulated by different levels of gene expression. Q RT- for some differentially expressed genes PCR detection, the trend of differential expression is consistent with the results of RNA-seq data analysis. The results of pathway enrichment analysis show that the main signaling pathways include MAPK signaling pathway, apoptosis and cell cycle related signaling pathways.
【學位授予單位】：重慶醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R734.2

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