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研究生：	郭昱廷 Kuo, Yu-Ting
論文名稱：	探討A20蛋白在胃癌進程中的作用 The role of A20 in gastric cancer progression
指導教授：	沈延盛 Shan, Yan-Shen
學位類別：	博士 Doctor
系所名稱：	醫學院 - 基礎醫學研究所 Institute of Basic Medical Sciences
論文出版年：	2024
畢業學年度：	112
語文別：	英文
論文頁數：	141
中文關鍵詞：	鐘擺化療法、胃癌、腫瘤壞死因子 α 誘導蛋白 3（TNFAIP3）、A20 、胱天蛋白酶 8 、自嗜相關蛋白 3 、微管相關 1A/1B-輕鏈 3 、癌症轉移、卵巢腫瘤（OTU）功能結構域、緊密蛋白 Occludin 、轉化蛋白 RhoA
外文關鍵詞：	metronomic chemotherapy, gastric cancer, tumor necrosis factor α induced protein 3, A20, caspase 8, ATG3, LC3, metastasis, OTU domain, Occludin, RhoA
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節拍化療 (MC) 是利用頻繁、低劑量的化療用於改善療效，但這類化療方法最終也會使癌細胞發展出化療抗藥性。慢性發炎是胃癌（GC）發展出化療抗性的重要危險因子。透過 mRNA 微陣列分析，我們發現了 TNFAIP3 (A20)，它與低度發炎和 GC 化療抗藥性有關，然而 A20 調節胃癌進展的分子機制仍不清楚。本研究旨在確定 A20 在胃癌中的分子機制與臨床意義。我們發現 A20 的表現量分別在順鉑（CDDP）、氟尿嘧啶（5-FU）和紫杉醇（PTX）的鐘擺療法耐藥性 AGS 胃癌細胞中增加；增加或減少 A20 影響了胃癌細胞的幹細胞特性與鐘擺化療法的抗藥性，此外我們還發現A20透過增強自嗜作用胃癌細胞在鐘擺化療法後的幹細胞特性。我們指出 A20 通過抑制 caspase 8 的活化來促進 ATG3 介導的自嗜作用。在 A20 的卵巢腫瘤（OTU）結構域中的功能喪失突變降低了 pro-caspase 8、ATG3 和 LC3 II 的表達，顯示 A20 調控的鐘擺化療抗藥性依賴於其 OTU 功能結構域。此外，我們指出 A20 促進胃癌細胞的遷移與轉移，在臨床相關性研究中，A20 的高表達與胃癌的侵略性相關，並被確認是胃癌的獨立風險因子，可用於預測患者的臨床結果和預後，機轉上，A20 造成了細胞緊密蛋白 Occludin 的丟失。實驗數據顯示 A20 通過其 OTU 結構域誘導 Occludin 內吞和溶酶體降解。使用 pull-down assay 的實驗顯示出 AO/OTUmut 影響 A20 與 RhoA 在 AGS 細胞中的結合，表明 A20 OTU 結構域活性對於 A20 與 RhoA 結合誘導 Occludin 的降解至關重要。總之，我們的研究表明A20通過胃癌在鐘擺化療中限制 caspase 8 的活化，進而穩定 ATG3 的表達，從而促進了幹細胞化與鐘擺化療抗藥性的形成。而 A20 透過增加 RhoA 的穩定性與活化，導致 Occludin 降解從而促進了胃癌細胞的轉移，是導致胃癌的不良預後的風險因素。我們的研究強調針對 A20 治療的重要性，可降低胃癌鐘擺化療的抗藥性與轉移，從而使患者的預後得到改善。

Metronomic chemotherapy (MC) employs frequent, low-dose chemotherapy to improve therapeutic efficacy; however, this approach can eventually lead to the development of chemoresistance in cancer cells. Chronic inflammation is a significant risk factor for chemoresistance in gastric cancer (GC). Through mRNA microarray analyses, we identified TNFAIP3 (A20), which is associated with low-grade inflammation and chemoresistance in GC. This study aimed to determine the molecular mechanisms and clinical significance of A20 in GC. The results showed that A20 expression contributed to the growth of MC-resistant cells. Manipulation of A20 expression affected changes in stemness properties and MC resistance in GC cells. Furthermore, we found that A20 facilitated GC stemness by promoting autophagy after MC. We revealed that A20 facilitated ATG3-mediated autophagy by inhibiting caspase 8. A loss-of-function mutation in the OTU domain of A20 reduced the expression of pro-caspase 8, ATG3, and LC3 II in AGS cells, indicating that A20-mediated MC resistance is dependent on its OTU domain. Moreover, we indicated that A20 promotes migration and metastasis of GC. In our clinical correlation study, high expression of A20 was associated with aggressive features and identified as a potential independent risk factor for GC patients. Mechanistically, A20 promoted the loss of Occludin tight junctions in GC cells. Furthermore, A20 was found to induce Occludin endocytosis and lysosomal degradation via its OTU domain. Using a pull-down assay, we identified that the migration-related protein RhoA interacts with A20. Additionally, an in situ proximity ligation assay showed that AO/OTUmut impaired the binding of A20 and RhoA in AGS cells, suggesting that the OTU domain activity of A20 is required for its binding with RhoA to induce Occludin degradation. In conclusion, our research demonstrates that A20 limits the activation of caspase 8 in GC during MC, which in turn stabilizes the expression of ATG3, promoting stemness and the development of chemoresistance. Furthermore, A20 increases the stability and activation of RhoA, resulting in the degradation of Occludin and promoting the metastasis of GC cells. This suggests that A20 is an independent risk factor for poor prognosis in GC. Our study highlights that A20 represents a novel therapeutic target for preventing GC metastasis and overcoming chemoresistance to MC, thereby improving patient outcomes.

中文摘要	I
Abstract	III
誌謝	V
Abbreviations list	VI
Content	VII
1. Chapter 1: Introduction	1
1.1. Gastric cancer	1
1.2. GC progression and metastasis	2
1.3. Chemotherapy treatment for GC	3
1.4. Metronomic chemotherapy (MC)	4
1.5. Chronic inflammation exerts malignant behaviors in GC	5
1.6. Tumor-associated macrophages (TAMs) orchestrate tumor-related inflammation in TME	5
1.7. The major factors contributing to chemoresistance: cancer stemness	6
1.8. Inflammation-driven cancer cells plasticity	7
1.9. Tumor necrosis factor alpha induced protein 3 (TNFAIP3, synonym A20)	8
1.10. The dual roles of A20 in cancer	9
1.11. Background and rationale	11
1.12. Hypothesis and specific aims	12
2. Chapter 2: Materials and Methods	13
2.1. Materials and reagents	13
2.2. Cell line and culture conditions	14
2.3. Co-culture system	15
2.4. MC treatment and MC-resistant cells establishment	15
2.5. Transformation and transfection A20 of in GC cell	16
2.6. TNF-α ELISA detection	17
2.7. Cell proliferation assay	17
2.8. Immunofluorescence staining	17
2.9. Colony formation assay (CFA)	18
2.10. Sphere formation assay (SFA)	18
2.11. Real-time PCR	18
2.12. Western blotting	18
2.13. Flow cytometry analysis	19
2.14. Apoptosis cell detection	19
2.15. Animal model	20
2.16. Immunoprecipitation (IP) assay and IP-MS	21
2.17. ATG3 cleavage assay	21
2.18. Transwell migration assay	22
2.19. Wound healing assay	22
2.20. Patients and specimens	23
2.21. Immunohistochemistry	23
2.22. Protein degradation analyses	24
2.23. Statistical analysis	24
3. Chapter 3: Results	26
3.1. A20 is upregulated in MC-resistant GC cells	26
3.2. A20 promotes MC-chemoresistance and reduces chemo-drugs sensitivity in GC cells	28
3.3. A20 contributes to GC stemness in GC cells during MC	30
3.4. A20-mediated autophagosome formation promotes resistance of GC cells to MC	30
3.5. A20 induces autophagy by upregulating and maintaining ATG3 expression in GC cells	31
3.6. A20 maintains ATG3 expression by blocking the caspase 8 cascade in GC cells during MC	32
3.7. A20-OTU domain regulates ATG3 expression via terminating of caspase 8 activation	33
3.8. A20 promotes GC cell migration ability to metastases	34
3.9. A20 is upregulated in the tumor tissue of GC	35
3.10. High A20 protein expression is associated with poor survival of GC patient	35
3.11. High A20 expression correlates to invasiveness and progression of GC	36
3.12. A20 promotes downregulation of tight junction protein occludin in GC	37
3.13. A20 induces Occludin degradation via endocytosis and lysosome action	38
3.14. A20 OTU domain mediates endocytosis and lysosomal degradation of Occludin	39
3.15. A20 OTU domain stabilizes RhoA expression to promote Occludin degradation	40
3.16. RhoA/ROCK2 signaling involves in A20-induced Occludin degradation	41
3.17. A20 OTU domain is critical for the interaction between A20 and RhoA	41
4. Chapter 4: Discussion and conclusion	44
5. Reference	53
Figures and Tables	72
Table 1. The primers for A20 mutagenesis	72
Table 2. The primers for Sanger sequencing of A20	73
Table 3. antibody list	74
Table 4 The primers for real-time PCR	75
Table 5 Demographic characteristics of GC patients in the full analysis set	76
Table 6 Correlation between A20 expression and clinicopathological profiles	77
Table 7 Univariate and multivariate analyses of survival in 122 GC patients.	78
Figure 1. A20 (TNFAIP3) expression is upregulated and associated with the inflammatory response after co-culture with U937 cells or chemodrug treatments	79
Figure 2. The upregulation of A20 is confirmed by Western blotting and quantitative PCR analysis	80
Figure 3. TNF-α facilitates MC resistance by upregulating A20 expression in GC	81
Figure 4. To establish chemoresistant AGS cells through MC treatments	82
Figure 5. TNF-α releasing and A20 expression upregulates by metronomic chemotherapy treatments	83
Figure 6. A20 contributes to cell growth in MC-resistant GC cell lines	84
Figure 7. Construction of A20 overexpression and knockdown GC cell lines	85
Figure 8. Manipulation of A20 expression affects the resistance of GC cells to chemotherapy	86
Figure 9. Knockdown of A20 inhibits tumor growth in both parental and 5-FU-MC-resistant MKN45 cells	87
Figure 10. A20 sustains cell proliferation in AGS cells during MC treatment	88
Figure 11. A20 reduces apoptotic cells in AGS cells during MC treatment	89
Figure 12. The tumoricidal effects of MTD and MC treatments in GC cell lines	90
Figure 13. A20 facilitates the stemness to promote resistance of GC cells to MC	91
Figure 14. A20 contributes to sphere forming ability and stemness in GC cells	92
Figure 15. A20 expression enhances autophagy formation in parental and resistant GC cell	93
Figure 16. A20 (red) co-localizes with LC3 (green) in AGS cells	94
Figure 17. A20 promotes GC stemness by increasing autophagy during MC	95
Figure 18. A20 induces autophagy formation by increasing ATG3 expression in GC cells	96
Figure 19. A20 induces autophagy and sustains stemness markers via ATG3 in GC cells	98
Figure 20. Knockdown of ATG3 suppresses cell growth and inhibits A20-promoted chemoresistance in MC-resistant AGS cells	99
Figure 21. A20 inhibits caspase-8 to maintain ATG3 expression in GC	100
Figure 22. Inhibition of caspase 8 increases ATG3 expression, autophagy and cell viability	101
Figure 23. Constructs of mutations on key amino acids of different A20 domains	102
Figure 24. A20 inactivates and de-ubiquitinates caspase 8 via its OTU domain	103
Figure 25. The A20 OTU domain sustains ATG3 expression by deubiquitinating and inactivating caspase 8 to promote autophagy during MC	104
Figure 26. A20 increases the wound healing ability of GC cells	105
Figure 27. A20 induces the transwell migration activity of GC cells	106
Figure 28. A20 increases the risk of GC metastasis in vivo.	107
Figure 29. A20 knockdown inhibits lung- and liver-metastasis of MKN45 tumor in NOD-SCID orthotopic model.	108
Figure 30. A20 is highly expressed in human gastric cancer cells	109
Figure 31. High expression of A20 negatively correlates to GC patient’s survival	110
Figure 32. High A20 expression contributes to GC aggressiveness and metastasis	111
Figure 33. A20 expression is associated with EMT in AGS and MKN45 cells	112
Figure 34. A20 is involved in the downregulation and cytoplasmic localization of Occludin in GC	113
Figure 35. A20 promotes the migration of GC cells by inducing the loss of Occludin	114
Figure 36. A20 contributes to Occludin degradation in AGS and MKN45 cells	115
Figure 37. A20 increases Occludin degradation through the lysosome system in GC cells	116
Figure 38. The loss of OTU domain function in A20 decreases the migration ability of AGS cells	117
Figure 39. A20 regulates Occludin endocytosis and lysosomal-translocation via its OTU domaim	118
Figure 40. RhoA is the most potentially A20 interacting protein for Occludin degradation	119
Figure 41. A20 upregulates RhoA expression in GC cells	120
Figure 42. A20 promotes occludin degradation and migration ability by stabilizing RhoA expression	121
Figure 43. A20 promotes occludin endocytic lysosome degradation by activating RhoA/ROCK2 pathway in GC	122
Figure 44. A20 interacts with RhoA by its OTU functional domain	123
Figure 45. A20 OTU domain facilitates RhoA activation and occludin translocation	124
Figure 46. Schematic diagram depicts the mechanism underlying A20-promoted cancer metastasis and MC resistance in GC	125
Curriculum vitae	126
                                    

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