研究證據顯示在癌細胞中NF-κB的持續活化，具有促進發炎、擴增癌幹細胞族群、促進腫瘤進展的作用。反之，最近的研究也顯示癌幹細胞中，因持續的NF-κB活化而有較高的發炎現象。此一作用可以促進發炎媒介物的表現與分泌，進而增強發炎作用和癌幹細胞特性，但是，這過程中的作用機制尚未清楚。在本研究中，我們使用生物資訊分析，發現在培養SAS口腔癌細胞株以形成癌幹細胞特性較高的tumorsphere的細胞中，伴隨NF-κB調控的發炎基因表現的上升；然而，COMMD1，一個腫瘤壞死因子α，介白素1β和類鐸受體訊號傳遞中，降低NF-κB活性的負調控分子的表現隨之下降。並行研究SAS口腔癌細胞株和來自人的和老鼠的H460和D121非小細胞肺癌細胞株，我們發現微核醣核酸205會調控COMMD1的三端非轉譯區，進而降低COMMD1訊息核糖核酸和蛋白質的表現。同時，微核醣核酸205的表現伴隨幹細胞特性增加而上升，並且受到NF-κB調控。在癌細胞中表現COMMD1可以促進RelA (p65)降解，抑制發炎刺激物引起的NF-κB活化，發炎性細胞激素的生成，和白血球的趨化移動。在癌細胞中以慢病毒感染產生shRNA，降低COMMD1的表現，則會增加幹細胞特性相關基因的表現，促進tumorsphere形成，以及增加細胞的不依賴貼附生長的轉形能力。腫瘤動物實驗顯示，降低COMMD1表現的癌細胞在老鼠體內有較高的腫瘤發生率和較快的腫瘤生長速度。並且發現由降低COMMD1表現的癌細胞所產生的腫瘤組織中，增加NF-κB的活化，發炎性和幹細胞特性相關基因的表現，並且具有較多的CD11b+發炎細胞和CD117+ 類幹細胞腫瘤細胞。這些研究結果顯示癌細胞中miR-205-COMMD1-NF-κB的正回饋途徑，可能是一項造成癌幹細胞中發炎並增強幹細胞特性的機制，進而促進腫瘤惡化。

Accumulating evidence indicates that sustained activation of NF-κB in cancer cells contributes to inflammation, expansion of tumor-initiating cancer stem cells (CSCs), and tumor progression. On the other hand, recent studies reveal that CSCs exhibit increased inflammation due to constitutive NF-κB activation, which is able to elevate expression and release of pro-inflammatory mediators into the tumor microenvironment and further increase stemness and inflammatory conditions in cancer cells. Nevertheless, the underlying molecular control is still ill-defined. In this study, we used bioinformatic analysis to show the upregulation of NF-κB-regulated proinflammatory genes and downregulation of Copper Metabolism (Murr1) Domain-containing 1 (COMMD1) during the enrichment of stemness in SAS head and neck squamous-cell carcinoma (HNSCC) cells. The 3′-UTR of COMMD1 mRNA consists of miR-205 target site. Parallel studies with SAS, human H460 and mouse D121 non–small-cell lung cancer cells indicated that miR-205 reduces COMMD1 expression, and the expression of miR-205 is upregulated upon NF-κB activation in stemness enriched cancer cells. COMMD1 effectively restrained inflammatory stimuli-induced NF-κB activation, cytokine production, as well as leukocytes migration. The lentiviral shRNA-mediated downregulation of COMMD1 in cancer cells increased the expression of stemness-associated genes, sphere-forming capacity, and potential for anchorage-independent growth. Moreover, study with cancer animal model showed that knockdown of COMMD1 enhances tumorigenesis and tumor growth. Tumors derived from COMMD1-knockdown cells displayed increased NF-κB activation and expression of inflammatory- and stemness-associated genes. In addition, expanded population of CD11b+ tumor-associated leukocytes and CD117+ stemness-enriched cancer cells were detected in these tumors. Overall, these results demonstrate that the miR-205-COMMD1-NF-κB axis forming a positive feedback loop for amplifying inflammatory- and stemness-associated properties in cancer cells is likely a underlying molecular mechanism for promoting the malignancy of tumors.

Table of Contents I
List of Figures V
List of Tables VIII
Abbreviations IX
Chinese abstract X
Abstract XII
Chapter 1 Introduction 1
1.1 Inflammation as a hallmark of tumor development 1
1.2 Tumor-initiating stem-like cells and cancer progression 2
1.3 Expansion of cancer stem cells due to activation of inflammatory signalings and NF-κB 3
1.4 Toll- like, IL-1β, and TNFα receptor signalings and inflammation 5
1.5 Negative regulators for maintaining homeostasis of inflammation 6
1.6 Ubiquitination in inflammatory signalings and activation of NF-κB and inflammation 7
1.7 Negative regulators of inflammatory signaling pathways that involve in the ubiquitination system 8
1.8 Structure and function of Copper metabolism gene MURR1-containing domain 1 (COMMD1) 11
1.9 MicroRNAs in inflammation and cancer development 14
Chapter 2 Materials and methods 15
2.1 Reagents and antibodies 15
2.2 Cell culture and enrichment of sphere-forming cancer cells 15
2.3 Bioinformatics analysis of microarray data, gene expression in tumor tissues, and miRNA target sites 16
2.4 Plasmid construction 16
2.5 Lentiviral shRNA, miR-205-sponge and precursor miR-205 construction 17
2.6 Lentiviral production and infection 17
2.7 Luciferase reporter assay 17
2.8 SDS-PAGE and immunoblot analysis 18
2.9 RT-qPCR analysis of gene and microRNA expression 18
2.10 Anchorage-independent growth assay 19
2.11 Macrophage recruitment assay 19
2.12 Flow cytometric analysis 20
2.13 In vivo tumorigenesis and tumor growth 20
2.14 Preparation of tumor single-cell suspension 20
2.15 Separation of CD117+ population from tumor single-cell suspension 21
2.16 Histological analysis 21
2.17 Statistical analysis 21
Chapter 3 Results 22
3.1 Elevated NF-κB activation and inflammation in stemness-enriched cancer cells 22
3.2 Identification of key regulators of NF-κB activation during enrichment for stemness 22
3.3 Downregulation of COMMD1 in stemness-enriched HNSCC cells and NSCLC cells 23
3.4 3’-UTR of COMMD1 mRNA contains miR-205 target site 23
3.5 Downregulation of COMMD1 by NF-κB-regulated miR-205 during enrichment for stemness 24
3.6 COMMD1 downregulation in cancer cells promotes inflammation 25
3.7 COMMD1 downregulation in cancer cells promotes macrophage recruitment 26
3.8 COMMD1 downregulation enhances stemness in cancer cells
3.9 COMMD1 downregulation enhances the transforming ability of cancer cells 27
3.10 COMMD1 downregulation promotes in vivo tumorigenicity and tumor growth 28
Chapter 4 Discussion 30
Chapter 5 References 34

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