慢性炎癥已被證實(shí)能夠在多種腫瘤中促進(jìn)腫瘤的發(fā)生與發(fā)展。在浸潤腫瘤間質(zhì)的免疫細(xì)胞中,巨噬細(xì)胞不僅是其中的主要成員,并且還能夠被腫瘤細(xì)胞“再教育”,替代性激活為2型腫瘤相關(guān)的巨噬細(xì)胞（M2巨噬細(xì)胞）。在炎癥相關(guān)的腫瘤發(fā)生過程中,激活的腫瘤相關(guān)巨噬細(xì)胞通過表達(dá)各種促炎癥因子來促進(jìn)腫瘤的發(fā)生。作為最重要的抑癌基因之一,p53（或稱Trp53,腫瘤轉(zhuǎn)化相關(guān)蛋白53）在幾乎一半的人類腫瘤樣本中因突變而失活,而在另一半樣本中,大多數(shù)p53通路被打斷。在正常的、沒有壓力信號的細(xì)胞中,p53蛋白水平由于受到其兩個(gè)主要負(fù)向調(diào)節(jié)因子MDM2、MDMX （MDM4）的調(diào)控而保持在一個(gè)非常低的濃度。而在原癌基因的激活、DNA損傷、炎癥、氧化壓力等應(yīng)激信號刺激下,p53通過以去MDM2和MDM4抑制作用為核心的翻譯后調(diào)控機(jī)制而被激活�；罨蟮膒53能發(fā)揮多種功能,包括調(diào)控細(xì)胞周期阻滯、凋亡、衰老等,從而阻斷了可能癌變的細(xì)胞增殖。盡管早期的大部分研究著眼于p53的細(xì)胞自主性功能的探索,p53在抑癌過程中還有非細(xì)胞自主性的功能：在腫瘤成纖維細(xì)胞或內(nèi)皮細(xì)胞中活化的p53能夠通過使細(xì)胞分泌因子影響相鄰細(xì)胞的生長和存活。除... 

【文章來源】：南京大學(xué)江蘇省 211工程院校 985工程院校 教育部直屬院校

【文章頁數(shù)】：125 頁

【學(xué)位級別】：博士

【文章目錄】：
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
致謝
Publications


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期刊論文
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[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)



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