肿瘤细胞分化为类神经细胞及其机制研究
发布时间：2021-01-26 23:27
肿瘤的发生被认为是处于活跃状态的正常细胞在基因错误调控后所产生的不可逆后果。同时该过程赋予了癌细胞重新分化的能力。新的证据表明,实体肿瘤细胞具有向神经细胞转化的能力。但目前,其机制尚不清楚。组蛋白和DNA修饰酶对染色质的动态调节是多种细胞命运特化的关键因素。大量的研究表明,诸多的表观遗传学因子参与到了肿瘤的发生发展当中来并在神经的发育过程中起着非常重要的作用,这其中就包括Enhancer of zeste homolog 2（EZH2）、DNA methyltransferase 1（DNMT1）、Histone deacetylase 1（HDAC1）、Lysine（K）-specificdemethylase 1A（LSD1）这四个表观遗传学蛋白因子。研究表明,包括H3K4me1/2/3、H3K27me1/2/3、H3K9ac等在内的组蛋白修饰和DNA甲基化的大量出现在维持神经干细胞干性方面起着重要作用。这类表观修饰的下降是促进神经干细胞向终端分化的重要因素。EZH2作为Polycomb repressive complex 2（PRC2）的酶活亚基,是催化H3K27me3形成、维...
【文章来源】：南京大学江苏省 211工程院校 985工程院校 教育部直属院校
【文章页数】：131 页
【学位级别】：博士
【文章目录】：
Abstract
中文摘要
Abbreviations
Chapter Ⅰ: Review: Epigenetics modification factors and signal pathways involve intumorigenesis and neurodevelopment
1. Tumorigenesis and development
2. Epithelial-to-mesenchymal transition（EMT）
3. Neurodevelopment
4. Cross-talk between tumors and nerves
5. Epigenetics modification
5.1 DNA methylation
5.2 Histone modifications and corresponding enzymes
5.2.1 Dynamic switch between methylation and demethylation in lysines ofhistones
5.2.2 Dynamic switch between acetylation and deacetylation in lysines ofhistones
5.3 Modifications in non-histone proteins
5.4 Relationship between epigenetics modifications and tumorigenesis
5.5 Relationship between epigenetics modifications and neurodevelopment
6. Signal pathways make critical role in tumorigenesis and neurodevelopment
6.1 Wnt/β-catenin pathway and its role in tumorigenesis and neurodevelopment
6.2 TGF-β pathway and its role in tumorigenesis and neurodevelopment
7. Summary
8. Reference
Chapter Ⅱ: Study on the differentiation of tumor cells into neuron-like cells and itsunderlying mechanism
1. Introduction
2. Materials and methods
3. Results and conclusion
3.1 Synergistic targeting at multiple of epigenetics modification enzymes can effectively inhibit tumor progression and promote neural-differentiation of tumors
3.1.1 Knockdown of chromatin modification enzymes inhibits tximor progression
3.1.2 Knockdown of chromatin modification enzymes induces neuron-like differentiation in cancer cell lines
3.1.3 Interactions between epigenetic modification enzymes and between the enzymes and the key signal transducers of TGF-β and Wnt pathway
3.1.4 Combined targeting at chromatin modification enzymes efficiently inhibit tumor progression and induces neuron-like differentiation of cancer cell line
3.1.5 Binding of epigenetic modification enzymes to promoters and chromatin modifications in the promoters are changed in cells treated with TALE
3.1.6 TALE treatment leads to neuronal differentiation in neural progenitor/stem cells
3.1.7 Conclusion
3.2 Knockdown of EZH2 leads to neuron-like differentiation in SW480 cells and reduce of malignancy
3.2.1 Knockdown of EZH2, but not other epigenetic modification factors, leads to neuron-like differentiation in SW480 cells
3.2.2 Knockdown of EZH2 downregulates protein expression of HDAC1, LSD1,DNMT1, and of P-CAT and SMAD transducers though Ub-dependent degradation way
3.2.3 Reduced EZH2 expression enhances ubiquitination of its interaction partners
3.2.4 EZH2 knockdown accelerates protein degradation and inhibits Wnt and TGF-psignaling transduction
3.2.5 EZH2 promotes expression of its interaction partners
3.2.6 EZH2 mediates maintaining stability of its interaction partners by coordinating with USP7
3.2.7 EZH2 plays central role in binding of epigenetic modification enzymes to target gene promoters
3.2.8 Conclusion
4. Discussion
5. Reference
Appendix
Publications
Acknowledgement
本文编号：3002004
【文章来源】：南京大学江苏省 211工程院校 985工程院校 教育部直属院校
【文章页数】：131 页
【学位级别】：博士
【文章目录】：
Abstract
中文摘要
Abbreviations
Chapter Ⅰ: Review: Epigenetics modification factors and signal pathways involve intumorigenesis and neurodevelopment
1. Tumorigenesis and development
2. Epithelial-to-mesenchymal transition（EMT）
3. Neurodevelopment
4. Cross-talk between tumors and nerves
5. Epigenetics modification
5.1 DNA methylation
5.2 Histone modifications and corresponding enzymes
5.2.1 Dynamic switch between methylation and demethylation in lysines ofhistones
5.2.2 Dynamic switch between acetylation and deacetylation in lysines ofhistones
5.3 Modifications in non-histone proteins
5.4 Relationship between epigenetics modifications and tumorigenesis
5.5 Relationship between epigenetics modifications and neurodevelopment
6. Signal pathways make critical role in tumorigenesis and neurodevelopment
6.1 Wnt/β-catenin pathway and its role in tumorigenesis and neurodevelopment
6.2 TGF-β pathway and its role in tumorigenesis and neurodevelopment
7. Summary
8. Reference
Chapter Ⅱ: Study on the differentiation of tumor cells into neuron-like cells and itsunderlying mechanism
1. Introduction
2. Materials and methods
3. Results and conclusion
3.1 Synergistic targeting at multiple of epigenetics modification enzymes can effectively inhibit tumor progression and promote neural-differentiation of tumors
3.1.1 Knockdown of chromatin modification enzymes inhibits tximor progression
3.1.2 Knockdown of chromatin modification enzymes induces neuron-like differentiation in cancer cell lines
3.1.3 Interactions between epigenetic modification enzymes and between the enzymes and the key signal transducers of TGF-β and Wnt pathway
3.1.4 Combined targeting at chromatin modification enzymes efficiently inhibit tumor progression and induces neuron-like differentiation of cancer cell line
3.1.5 Binding of epigenetic modification enzymes to promoters and chromatin modifications in the promoters are changed in cells treated with TALE
3.1.6 TALE treatment leads to neuronal differentiation in neural progenitor/stem cells
3.1.7 Conclusion
3.2 Knockdown of EZH2 leads to neuron-like differentiation in SW480 cells and reduce of malignancy
3.2.1 Knockdown of EZH2, but not other epigenetic modification factors, leads to neuron-like differentiation in SW480 cells
3.2.2 Knockdown of EZH2 downregulates protein expression of HDAC1, LSD1,DNMT1, and of P-CAT and SMAD transducers though Ub-dependent degradation way
3.2.3 Reduced EZH2 expression enhances ubiquitination of its interaction partners
3.2.4 EZH2 knockdown accelerates protein degradation and inhibits Wnt and TGF-psignaling transduction
3.2.5 EZH2 promotes expression of its interaction partners
3.2.6 EZH2 mediates maintaining stability of its interaction partners by coordinating with USP7
3.2.7 EZH2 plays central role in binding of epigenetic modification enzymes to target gene promoters
3.2.8 Conclusion
4. Discussion
5. Reference
Appendix
Publications
Acknowledgement
本文编号：3002004
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