髓系细胞P53/MDM2-MDM4信号网络对肿瘤发生以及肿瘤转移的调控研究
发布时间：2021-10-20 17:38
慢性炎症已被证实能够在多种肿瘤中促进肿瘤的发生与发展。在浸润肿瘤间质的免疫细胞中,巨噬细胞不仅是其中的主要成员,并且还能够被肿瘤细胞“再教育”,替代性激活为2型肿瘤相关的巨噬细胞（M2巨噬细胞）。在炎症相关的肿瘤发生过程中,激活的肿瘤相关巨噬细胞通过表达各种促炎症因子来促进肿瘤的发生。作为最重要的抑癌基因之一,p53（或称Trp53,肿瘤转化相关蛋白53）在几乎一半的人类肿瘤样本中因突变而失活,而在另一半样本中,大多数p53通路被打断。在正常的、没有压力信号的细胞中,p53蛋白水平由于受到其两个主要负向调节因子MDM2、MDMX （MDM4）的调控而保持在一个非常低的浓度。而在原癌基因的激活、DNA损伤、炎症、氧化压力等应激信号刺激下,p53通过以去MDM2和MDM4抑制作用为核心的翻译后调控机制而被激活。活化后的p53能发挥多种功能,包括调控细胞周期阻滞、凋亡、衰老等,从而阻断了可能癌变的细胞增殖。尽管早期的大部分研究着眼于p53的细胞自主性功能的探索,p53在抑癌过程中还有非细胞自主性的功能：在肿瘤成纤维细胞或内皮细胞中活化的p53能够通过使细胞分泌因子影响相邻细胞的生长和存活。除...
【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】：125 页
【学位级别】：博士
【文章目录】：
Abstract
中文摘要
Abbreviations/Acoronyms
Chapter Ⅰ: A Brief Review:Tumor Suppressor p53:A Novel Link between Inflammation and Cancer
1.1 Introduction
1.2 Chronic Inflammation and Colorectal Cancer Development
1.2.1 Chronic Inflammation and Colorectal Cancer Initiation
1.2.2 Chronic Inflammation and Colorectal Cancer Promotion
1.2.3 Chronic Inflammation and Colorectal Cancer Metastasis
1.3 Macrophages in Inflammation-Associated Cancer
1.3.1 Origin, Maturation of Macrophages
1.3.2 Main Signaling between Macrophages and Malignant Cells
1.3.3 Alternative Activation of Macrophages
1.3.4 Alternatively Activated Macrophages in Tumors
1.4 Cell-Autonomous Functions of Tumor Suppressor p53
1.4.1 Functional Roles of Tumor Suppressor p53
1.4.2 Regulation of p53 Stability by MDM2/MDMX Proteins
1.5 p53 and Inflammation
1.5.1 p53 is a Suppressor of Inflammatory Response
1.5.2 Mechanisms Linking p53 and Inflammation
1.6 Non-Cell Autonomous Tumor Suppression Functions of p53 in Tumor Microenvironment
1.7 Summary and prospective
Reference
Chapter Ⅱ: Materials and Methods
Reference
Chapter Ⅲ: Regulation of p53/MDM2-MDM4 Network in Myeloid Lineage Affects Tumorigenesis and Tumor Metastasis
Summary
Introduction
RESULTS
3.1 p53 Signaling in the Myeloid Lineage was Critical for Protection against Inflammation and Inflammation-Associated Tumorigenesis
3.1.1 Generation of Mice with Myeloid Specific Deletion of p53
3.1.2 p53 Deficiency Led to Enhanced Inflammatory Responses in vitro
3.1.3 Insufficiency of p53 in Myeloid Lineage Accelerated Tumor Progression in Apc~(Min/+) Mice
3.1.4 Proinflammatory Cytokines and Mediators were Significantly Increased in the Tumors of Ape~(Min/+）; LysM-p53~(Flox/+) Mice
3.2 Generation of Mice with Myeloid Specific Activation of p53
3.2.1 Normal Development in LysM-MM Mice
3.2.2 Recombination Detections on LysM-MM Mice
3.2.3 Elevated Expression Level of p53 in Myeloid Cells from LysM-MM Mice had no Effect on Cell Fate and Differentiation
3.3 LysM-MM Mice were More Resistant to Inflammatory Stimuli
3.3.1 Activation of p53 Dampened Response to Inflammatory Stimuli in Macrophages in vitro
3.3.2 p53 was Activated Specifically in Myeloid Cells at Inflamed Sites of Colon
3.3.3 LysM-MM Mice were More Resistant to DSS-Induced Colitis
3.3.4 Dampened Inflammatory Responses which Drives Hyperplasia and Tumorigenesis in LysM-MM Mice
3.4 Attenuated Inflammation-Associated Tumorigenesis and Tumor Progression in LysM-MM Mice
3.4.1 Decreased Tumor Formation in Apc~(Min/+); LysM-MM Mice
3.4.2 Blocked Tumor Growth by Increased Apoptosis and Reduced Proliferation in Apc~(Min/+); LysM-MM Tumors
3.4.3 Suppressed Proinflammatory Cytokines and Mediators in Tumors of Apc~(Min/+); LysM-MM Mice
3.4.4 Delayed Tumor Development in DSS Treated Apc~(Min/+); LysM-MM Mice
3.4.5 ysM-MM Mice were More Resistant to Colitis-Associated Tumorigenesis
3.5 Myeloid-Specific Activation of p53 Retarded Pulmonary Metastasis of MMTV-PyMT Breast Cancer
3.5.1 Breast Tumor Initiation and Growth in PyMT; CTR and PyMT; LysM-FM/+ Mice
3.5.2 Pulmonary Metastasis in PyMT; CTR and PyMT; LysM-FM/+ Mice
3.6 p53 was involved in Regulating Alternative Activation Genes of Macrophages
3.6.1 p53 in Myeloid Lineage was Involved in Regulating Alternative Activation Genes in Apc~(Min/+) Tumors
3.6.2 Reduced M2 TAMs Infiltration into MMTV-PyMT; LysM-FM/+ Tumors
3.6.3 Activation of p53 Dampened IL-4 Induced M2 Polarization in vitro
3.6.4 Regulation of Macrophages Polarization by Activation of p53 was Associated with Elevated miR-34s and Suppression of c-Myc
Summary and Discussion
Appendix 1
Appendix 2
Reference
致谢
Publications
【参考文献】：
期刊论文
[1]Risk for colorectal cancer in ulcerative colitis:Changes,causes and management strategies[J]. Peter Laszlo Lakatos,Laszlo Lakatos. World Journal of Gastroenterology. 2008(25)
[2]Dextran sulfate sodium-induced colitis-associated neoplasia:a promising model for the development of chemopreventive interventions[J]. Margie Lee CLAPPER,Harry Stanley COOPER,Wen-Chi Lee CHANG. Acta Pharmacologica Sinica. 2007(09)
本文编号：3447323
【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】：125 页
【学位级别】：博士
【文章目录】：
Abstract
中文摘要
Abbreviations/Acoronyms
Chapter Ⅰ: A Brief Review:Tumor Suppressor p53:A Novel Link between Inflammation and Cancer
1.1 Introduction
1.2 Chronic Inflammation and Colorectal Cancer Development
1.2.1 Chronic Inflammation and Colorectal Cancer Initiation
1.2.2 Chronic Inflammation and Colorectal Cancer Promotion
1.2.3 Chronic Inflammation and Colorectal Cancer Metastasis
1.3 Macrophages in Inflammation-Associated Cancer
1.3.1 Origin, Maturation of Macrophages
1.3.2 Main Signaling between Macrophages and Malignant Cells
1.3.3 Alternative Activation of Macrophages
1.3.4 Alternatively Activated Macrophages in Tumors
1.4 Cell-Autonomous Functions of Tumor Suppressor p53
1.4.1 Functional Roles of Tumor Suppressor p53
1.4.2 Regulation of p53 Stability by MDM2/MDMX Proteins
1.5 p53 and Inflammation
1.5.1 p53 is a Suppressor of Inflammatory Response
1.5.2 Mechanisms Linking p53 and Inflammation
1.6 Non-Cell Autonomous Tumor Suppression Functions of p53 in Tumor Microenvironment
1.7 Summary and prospective
Reference
Chapter Ⅱ: Materials and Methods
Reference
Chapter Ⅲ: Regulation of p53/MDM2-MDM4 Network in Myeloid Lineage Affects Tumorigenesis and Tumor Metastasis
Summary
Introduction
RESULTS
3.1 p53 Signaling in the Myeloid Lineage was Critical for Protection against Inflammation and Inflammation-Associated Tumorigenesis
3.1.1 Generation of Mice with Myeloid Specific Deletion of p53
3.1.2 p53 Deficiency Led to Enhanced Inflammatory Responses in vitro
3.1.3 Insufficiency of p53 in Myeloid Lineage Accelerated Tumor Progression in Apc~(Min/+) Mice
3.1.4 Proinflammatory Cytokines and Mediators were Significantly Increased in the Tumors of Ape~(Min/+）; LysM-p53~(Flox/+) Mice
3.2 Generation of Mice with Myeloid Specific Activation of p53
3.2.1 Normal Development in LysM-MM Mice
3.2.2 Recombination Detections on LysM-MM Mice
3.2.3 Elevated Expression Level of p53 in Myeloid Cells from LysM-MM Mice had no Effect on Cell Fate and Differentiation
3.3 LysM-MM Mice were More Resistant to Inflammatory Stimuli
3.3.1 Activation of p53 Dampened Response to Inflammatory Stimuli in Macrophages in vitro
3.3.2 p53 was Activated Specifically in Myeloid Cells at Inflamed Sites of Colon
3.3.3 LysM-MM Mice were More Resistant to DSS-Induced Colitis
3.3.4 Dampened Inflammatory Responses which Drives Hyperplasia and Tumorigenesis in LysM-MM Mice
3.4 Attenuated Inflammation-Associated Tumorigenesis and Tumor Progression in LysM-MM Mice
3.4.1 Decreased Tumor Formation in Apc~(Min/+); LysM-MM Mice
3.4.2 Blocked Tumor Growth by Increased Apoptosis and Reduced Proliferation in Apc~(Min/+); LysM-MM Tumors
3.4.3 Suppressed Proinflammatory Cytokines and Mediators in Tumors of Apc~(Min/+); LysM-MM Mice
3.4.4 Delayed Tumor Development in DSS Treated Apc~(Min/+); LysM-MM Mice
3.4.5 ysM-MM Mice were More Resistant to Colitis-Associated Tumorigenesis
3.5 Myeloid-Specific Activation of p53 Retarded Pulmonary Metastasis of MMTV-PyMT Breast Cancer
3.5.1 Breast Tumor Initiation and Growth in PyMT; CTR and PyMT; LysM-FM/+ Mice
3.5.2 Pulmonary Metastasis in PyMT; CTR and PyMT; LysM-FM/+ Mice
3.6 p53 was involved in Regulating Alternative Activation Genes of Macrophages
3.6.1 p53 in Myeloid Lineage was Involved in Regulating Alternative Activation Genes in Apc~(Min/+) Tumors
3.6.2 Reduced M2 TAMs Infiltration into MMTV-PyMT; LysM-FM/+ Tumors
3.6.3 Activation of p53 Dampened IL-4 Induced M2 Polarization in vitro
3.6.4 Regulation of Macrophages Polarization by Activation of p53 was Associated with Elevated miR-34s and Suppression of c-Myc
Summary and Discussion
Appendix 1
Appendix 2
Reference
致谢
Publications
【参考文献】：
期刊论文
[1]Risk for colorectal cancer in ulcerative colitis:Changes,causes and management strategies[J]. Peter Laszlo Lakatos,Laszlo Lakatos. World Journal of Gastroenterology. 2008(25)
[2]Dextran sulfate sodium-induced colitis-associated neoplasia:a promising model for the development of chemopreventive interventions[J]. Margie Lee CLAPPER,Harry Stanley COOPER,Wen-Chi Lee CHANG. Acta Pharmacologica Sinica. 2007(09)
本文编号：3447323
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