臺灣博碩士論文加值系統

腫瘤微環境對於腫瘤生長與轉移，扮演著相當重要之角色。然而，癌細胞如何調控微環境中細胞與非細胞物質之機制，至今仍未完全明瞭。 PML為一腫瘤抑制蛋白，許多研究指出PML具有多方面抑制腫瘤生長及特性的相關能力，並且在許多不同種類的腫瘤中，其表現量有降低的情形；但是目前PML對於腫瘤微環境調控之探討，仍然相當不足。在本篇論文中，我們發現WDR4可作為受質辨識器(substrate adaptor)，並與Cullin4、Roc1和DDB1蛋白形成連接酶(E3 ligase)，將PML進行多次泛素化 (polyubiquitination)，並且降解PML。臨床上的證據也顯示出在肺癌中，WDR4/PML的作用路徑有高度活化之現象，並且此路徑的高度活化與病人不良的預後有相關性。接著我們想研究WDR4/PML路徑在肺癌進程中的生物意義，因此我們利用基因微陣列分析發現，WDR4/PML可誘導一群細胞表面蛋白或是分泌蛋白之表現，它們分別是CD73、uPAR及SAA2。藉由在生物體外(in vitro)及動物實驗，我們發現WDR4/PML可透過這些誘導出的下游基因，促進肺癌細胞移動、侵襲和轉移之能力。此外，我們利用異體移植動物實驗和基因轉殖小鼠模式，觀察到WDR4/PML會增加入侵腫瘤內的調控性T細胞 (Tregs)與腫瘤相關巨噬細胞 (M2-like macrophages)之數目，但降低細胞毒殺性T細胞(CD8+ cytotoxic T lymphocytes)之數目；因此WDR4/PML作用路徑，可以創造出一個免疫抑制的腫瘤微環境；然而，此一現象卻可以被CD73抑制劑所抑制。整體來說，我們發現WDR4是一個新興致癌蛋白，可以透過多次泛素化以降解PML，此調控會創造出免疫抑制及促進癌細胞轉移之腫瘤微環境；此研究也顯示未來在治療PML不正常降解之肺癌時，也許可以使用免疫調控之方式，以達到治療效果。

The tumor microenvironment plays an important role in tumor growth and metastasis. However, the mechanism by which tumor cells regulate the cell and non-cell constituents of surrounding stroma remains incompletely understood. PML is a pleiotropic tumor suppressor but its role in tumor microenvironment regulation is poorly characterized. PML protein is frequently downregulated in many cancer types, including lung cancer. Here, we identify a novel PML ubiquitination/destruction pathway mediated by ubiquitin ligase CRL4WDR4. Clinically, this PML destruction pathway is hyperactivated in lung cancer and correlates with poor prognosis. The WDR4/PML axis induces a set of cell surface or secreted factors, including CD73, uPAR, and SAA2, which elicit paracrine effects to stimulate migration, invasion, and metastasis in multiple lung cancer models. Furthermore, in both xenograft and genetically engineered mouse models, the WDR4/PML axis elevates intratumoral Tregs and M2-like macrophages and reduces CD8+ T cells to promote lung tumor growth and these immunosuppressive effects are all reversed by CD73 blockade. Our study identifies WDR4 as a novel oncoprotein which negatively regulates PML via ubiquitination to promote lung cancer progression by fostering an immunosuppressive and pro-metastatic tumor microenvironment and suggests a potential of immune-modulatory approaches for treating lung cancer with aberrant PML degradation.

中文摘要 i
Abstract ii
Introduction 1
1. Ubiquitin-proteasome system 1
1.1 E3 ubiquitin ligase 2
1.2 Cullin-RING E3 ligase 3
1.3 DCAFs 4
2. WDR4 6
3. Promyelocytic leukemia protein (PML) 7
3.1 Roles of PML in tumor suppression and beyond 8
3.2 Functions of PML in tumor suppression 9
3.2.1 Regulation of cellular senescence 9
3.2.2 Regulation of apoptosis 10
3.2.3 Regulation of neoangiogenesis 11
3.2.4 Regulation of cell migration, invasion and metastasis 12
3.3 Regulation of PML expression in human cancers 12
3.3.1 RNF4-mediated PML ubiquitination 13
3.3.2 E6AP-mediated PML ubiquitination 13
3.3.3 Pin1/KLHL20-mediated PML ubiquitination 14
3.3.4 PIAS1/CK2-dependent PML ubiquitination 15
3.3.5 ERK2/Pin1-dependent PML degradation 15
3.3.6 Other ubiquitin E3 ligase for PML degradation 16
3.3.7 USP11-dependent PML deubiquitination 16
3.4 Roles of PML in viral infection, innate and adaptive immunity, and cytokine production 17
4. Tumor microenvironment and metastasis 18
4.1 Chronic inflammation, immunity, and cancer 19
4.2 Roles of immune cells in microenvironmental regulation of tumor progression 20
4.2.1 Regulatory T cells (Tregs) 20
4.2.2 Myeloid-derived suppressor cells (MDSCs) 22
4.2.3 Tumor-associated Macrophages (TAMs) 23
4.2.4 Tumor-associated Neutrophils (TANs) 25
4.2.5 Dendritic cells (DCs) 26
4.2.6 Nature killer (NK) cells 26
4.3 Roles of downstream targets of WDR4/PML axis in tumor progression and metastasis 28
4.3.1 CD73 28
4.3.1.1 Role of CD73 in regulation of cancer immunity 29
4.3.1.2 Role of CD73 in tumor metastasis 29
4.3.2 Urokinase-type plasminogen activator receptor (uPAR) 30
4.3.2.1 Proteolytic function of uPAR in cancer 31
4.3.2.2 Non-proteolytic function of uPAR in cancer 31
4.3.3 Serum amyloid A (SAA) 32
Background and significance 34
Material and methods 36
Cell culture 36
Plasmids 36
Antibodies and reagents 36
RT/qPCR 37
RNA interference and lentivirus transduction 37
Western blotting, immunoprecipitation, and GST pull down 37
Ubiquitination assays 38
Microarray 38
CM preparation 38
MMP activity assay 38
Migration and invasion assays 39
Proliferation assay 39
Animal experiments 40
Histology and IHC analyses 40
Human specimens 41
Flow cytometry 41
Bioinformatics 42
Statistical analysis 42
Study approval 43
Results 44
Identification of CRL4WDR4 as a PML ubiquitin ligase 44
WDR4 promotes PML proteasomal degradation 45
WDR4/PML axis is hypeactivated in lung cancer and correlates with poor prognosis 46
WDR4/PML axis induces a set of tumor-promoting factors 47
WDR4/PML axis promotes lung cancer migration and invasion 49
WDR4/PML axis promotes lung cancer metastasis 50
WDR4/PML axis induces an immunosuppressive tumor microenvironment 51
WDR4 acts through CD73 to suppress anti-tumor immunity 52
Discussion 55
Reference 61
Figures 80
Figure 1. CRL4 is involved in PML ubiquitination. 80
Figure 2. WDR4 regulates PML ubiquitination. 81
Figure 3. WDR4 functions as a CRL4 substrate adaptor which promotes PML ubiquitination. 82
Figure 4. WDR4 can promote the ubiquitination of PML S565A mutant. 83
Figure 5. WDR4 bridges PML and Cul4 E3 ligase complexes. 84
Figure 6. WDR4 directly interacts with PML, and CRL4WDR4 functions as a novel ubiquitin ligase for PML. 85
Figure 7. WDR4 promotes PML degradation. 86
Figure 8. WDR4 knockdown increases PML level in multiple cell types. 87
Figure 9. WDR4 promotes PML proteasomal degradation. 88
Figure 10. WDR4 upregulation correlates with poor prognosis in lung cancer. 89
Figure 11. The expression of WDR4 is inverse correlated with that of PML and patient survival in lung cancer. 90
Figure 12. WDR4/PML axis induces a set of tumor-promoting factors. 92
Figure 13. CD73, uPAR and SAA2 are upregulated by WDR4 overexpression and PML knockdown in lung cancer cell lines. 93
Figure 14. CD73, uPAR and SAA2 are downstream effectors for the WDR4/PML axis. 94
Figure 15. The clinical relevance of CD73, uPAR and SAA2 in lung cancer. 95
Figure 16. WDR4 promotes lung cancer migration and invasion in vitro, which is reversed by PML knockdown. 97
Figure 17. WDR4/PML axis facilitates lung cancer migration and invasion in vitro. 98
Figure 18. The migration/invasion-promoting functions of WDR4 are also attenuated by overexpression of PML-I. 99
Figure 19. The contribution of CD73/uPAR/SAA2 induction to WDR4/PML axis-promoted lung cell migration and invasion. 100
Figure 20. CM derived from cells coexpressed PML-I with WDR4 suppress WDR4-promoted migration and invasion of parental lung cancer cells. 101
Figure 21. Depletion of CD73, uPAR or SAA2 each attenuated the paracrine effect of WDR4 on stimulating migration and invasion. 102
Figure 22. Coexpressed PML-IV or PML-I with WDR4 suppress WDR4-promoted lung cancer metastasis in vivo. 103
Figure 23. WDR4 knockdown in A549 cells and patient-derived primary lung cancer cells (CL152) suppresses lung metastasis, which is completely reversed by PML knockdown. 105
Figure 24. WDR4/PML axis does not regulate cell proliferation of mouse LLC1 cells in vitro. 107
Figure 25. WDR4/PML axis promotes lung cancer metastasis and also induces downstream effectors in a syngeneic mouse model. 108
Figure 26. WDR4/PML axis regulates cell proliferation and tumor growth in vivo. 110
Figure 27. The roles of WDR4/PML axis in regulating intratumoral immune cells in a syngeneic mouse model. 111
Figure 28. WDR4/PML axis induces an immunosuppressive tumor microenvironment in a syngeneic mouse model. 112
Figure 29. A role of WDR4/PML axis in fostering an immunosuppressive tumor microenvironment. 113
Figure 30. WDR4/PML axis also induces downstream effectors in GEMM for human lung adenocarcinoma. 115
Figure 31. WDR4 ablation suppresses p53-deficiency/K-Ras-driven lung tumorigenesis. 116
Figure 32. WDR4 deficiency impairs lung tumor formation and progression. 117
Figure 33. WDR4 deficiency prolongs survival rate of mice. 118
Figure 34. WDR4 ablation creates anti-tumor microenvironment. 119
Figure 35. WDR4 deficiency enhances the population of tumor-infiltrating CD8+ CTLs, whereas reduces that of Tregs in lung tumors. 120
Figure 36. WDR4 ablation reduces the population of tumor-infiltrating M2-like macrophages in lung tumors. 122
Figure 37. PD-1 expression on Tregs and CD8+ T cells is decreased in WDR4-deficient lung tumors of GEMM. 123
Figure 38. Blockade of CD73 suppresses cell proliferation and reduces tumor burden in lung tumor of GEMM. 124
Figure 39. WDR4 ablation suppresses p53-deficiency/K-Ras-driven lung tumorigenesis by inhibiting CD73-dependent immunosuppressive functions. 125
Figure 40. Model for WDR4-mediated PML degradation and its impacts on tumor microenvironment. 126
Appendixes 127
Appendix 1. Screen for Cul4 substrate adaptors that regulate PML-I ubiquitination. 127
Appendix 2. WDR4 regulates PML ubiquitination. 128
Appendix 3. R219A mutant of WDR4 is defect in the ability for autoubiquitination and PML ubiquitination 129
Appendix 4. Identification of the region in WDR4 responsible for PML binding. 130
Appendix 5. dTL1, the PML-binding mutant of WDR4, cannot promote PML ubiquitination. 132
Appendix 6. R219A and dTL1 mutants of WDR4 cannot promote PML degradation. 133
Appendix 7. WDR4 reduces PML half-life. 134
Appendix 8. WDR4 R219A and dTL1 mutants do not significantly elevate the expression of CD73, uPAR and SAA2. 135
Appendix 9. CD73, uPAR and SAA2 are downstream effectors for the WDR4/PML axis. 136
Appendix 10. Hypoxia induces SAA2 expression in a HIF-1 dependent manner. 137
Appendix 11. WDR4/PML axis regulates CD73, uPAR and SAA2 through HIF-1. 138
Appendix 12. The activities of MMP2 and MMP9 are consistently upregulated by WDR4 overexpression and PML knockdown. 139
Appendix 13. WDR4 promotes lung cancer migration and invasion in vitro, which is reversed by PML knockdown. 140
Appendix 14. WDR4/PML axis facilitates lung cancer migration and invasion in vitro. 141
Appendix 15. The contribution of CD73/uPAR/SAA2 induction to WDR4/PML axis-promoted lung cell migration and invasion. 142
Appendix 16. WDR4/PML axis confers an environment beneficial for migration and invasion of lung cancer cells. 143
Appendix 17. CM derived from cells coexpressed PML-IV with WDR4 suppress WDR4-promoted migration and invasion of parental lung cancer cells. 144
Table 1: Summary of the IHC data of WDR4 expression in various malignant and benign tumors 145
Table 2: Information for antibodies used in this study 146
Table 3: Primers for quantitative PCR and mouse genotyping 148
Table 4: Targeting sequences for siRNAs and shRNAs 150
Table 5: Clinical pathological characteristics of lung cancer patients 151

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