博碩士論文 105886604 詳細資訊




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姓名 阮氏梅香(Nguyen Thi Mai Huong)  查詢紙本館藏   畢業系所 系統生物與生物資訊研究所
論文名稱 研究miR-524-5p和miR-567治療在黑色素瘤與BRAF抑製劑的抗藥性黑色素瘤
(Study of miR-524-5p and miR-567 in the progression of melanoma and BRAF inhibitor-resistant melanoma)
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摘要(中) 現在有許多在黑色素瘤治療的發展,例如靶向治療和免疫治療;但部分患者對於治療沒有效或對這些治療產生抗藥性。因此,需要開發一種替代策略,可進一步提高臨床效益。目前已知MAPK/ERK 路徑在黑色素瘤的發展中為主要作用。我們先前微陣列晶片 (microarray) 實驗的結果觀察到有 22 種miRNAs與 MAPK/ERK 訊息路徑有關。在此論文研究兩個miRNAs為miR-524-5p 和 miR-567 ,並想了解在黑色素瘤以及 BRAF 抑製劑的抗藥性黑色素瘤中功能影響。
我們之前的研究表明, miR-524-5p 的過度表現,可抑制黑色素瘤細胞增殖。然而,miR-524-5p在BRAF抑製劑的抗藥性黑色素瘤中功能及機制仍然未知。因此,在本研究中,首先我們專注於 miR-524-5p 在 BRAF 抑製劑的抗藥性黑色素瘤細胞中的功能。我們的數據顯示,接受 BRAF 抑製劑治療為完全治癒 (complete response) 和長期治療後復發 (long-term partial response) 的患者中 miR-524-5p 的表現量與短期治療後復發 (short-term partial response) 患者相比更高。此發現證明 miR-524-5p 參與黑色素瘤患者對 BRAF 抑製劑的反應。值得注意的是,miR-524-5p 的過度表現抑制黑色素瘤細胞和動物實驗的發展。在抗藥性細胞中觀察到 MAPK/ERK 訊息路徑的重新激活,並且 miR-524-5p 的過度表現抑制抗藥性細胞中磷酸化的MEK1/2 和 ERK1/2訊息路徑的活性。
miR-567為另一個有潛力的 miRNA ,表現量在黑色素瘤細胞和組織中與黑色素細胞和痣相比較低 。值得注意的是,與 miR-524-5p 的染色結果相比,miR-567 的染色表現更準確地區分黑色素瘤和痣組織。 miR-567的過度表現顯著抑制黑色素瘤細胞增殖、存活、非貼附性的生長、遷移和侵襲能力。此外, 將黑色素瘤細胞中miR-567 直接調控 IGF1R、E2F1 和 Cyclin基因減弱 (knockdown),可抑制細胞的增殖和存活。有趣的是,可藉由miR-567 的過度表現下調黑色素瘤細胞中的 MAPK/ERK 和 PI3K/AKT訊息路徑。此外,miR-567的過度表現抑制巨噬細胞誘導黑色素瘤細胞所促使腫瘤生長。
以上所述為此研究對 miR-524-5p 和 miR-567 調控黑色素瘤發生和 BRAF 抑製劑的抗藥性在生物上作用和機制更加暸解。研究結果顯示,miR-524-5p 和 miR-567 不僅可以作為生物標誌物,也可作為預防黑色素瘤進展的潛在分子靶點。
摘要(英) Even more advancements in the treatment of melanoma such as target therapy and immunotherapy are now available; unfortunately, a subset of patients do not benefit or produced resistance to these approaches. Therefore, an urgent need to develop an alternative strategy should be investigated to further improve clinical benefits. It is well established that MAPK/ERK pathway plays a major role in the progression of melanoma. Interestingly, our previous microarray result observed that there are 22 miRNAs related to the status of MAPK/ERK pathway. In this context, we were interested in the functions of two candidate miRNAs, miR-524-5p and miR-567, in the development of melanoma and BRAF inhibitor-resistant melanoma.
Our previous study showed that overexpression of miR-524-5p reduced the development of melanoma cells. However, the biological functions of miR-524-5p and its mechanism underlying BRAF inhibitor resistance are still unknown. Therefore, in this study, we focused on the functions of miR-524-5p in BRAF inhibitor-resistant melanoma cells. The results showed that expression of miR-524-5p was higher in complete response and long-term partial response as compared to short-term partial response and progressive disease in patients treated with BRAF inhibitors. This finding suggested that miR-524-5p was involved in the response of melanoma patients to BRAF inhibitors. Of note, overexpression of miR-524-5p reduced the development of melanoma in vivo and in vitro. Reactivation of MAPK/ERK pathway was observed in resistant cells and overexpression of miR-524-5p downregulated the activity of this pathway by decreasing the phosphorylation of MEK1/2 and ERK1/2.
Expression of miR-567, another potential miRNA candidate, was decreased in melanoma cells and melanoma tissues as compared to melanocyte cells and nevus tissues. Of note, staining expression of miR-567 was more accurately differentiate between melanoma and nevus tissues as compared to staining of miR-524-5p. Overexpression of miR-567 in melanoma cells significantly reduced proliferation, survival, anchorage-independent growth, migratory, and invasive abilities. In addition, knockdown of miR-567 direct targets, IGF1R, E2F1, and Cyclin B2, attenuated proliferation and survival of melanoma cells. Interestingly, introduction of miR-567 downregulated MAPK/ERK and PI3K/AKT pathways in melanoma cells. Moreover, overexpression of miR-567 reduced the promoting tumor growth of melanoma cells induced by macrophages, indicating the involvement of miR-567 in tumor microenvironment.
In conclusion, these results increased the knowledge about the biological roles and mechanisms underlying miR-524-5p and miR-567 mediated tumorigenesis and BRAF inhibitor resistance. The findings suggested that miR-524-5p and miR-567 could be served not only as biomarkers but also as potential molecular targets for prevention of melanoma progression.
關鍵字(中) ★ 黑色素瘤
★ BRAF抑製劑
★ 抗藥性
★ 微型RNA
關鍵字(英) ★ Melanoma
★ BRAF inhibitor
★ Resistant
★ microRNA
論文目次 Abstract i
中文摘要 iii
Acknowledgement v
List of Figures xi
List of Tables xiv
List of Abbreviations xiv
Chapter 1 1
Literature review 1
1.1. Melanoma 1
1.2. Gene mutations in melanoma and related pathways 2
1.3. Diagnosis and treatment of melanoma 4
1.3.1. Diagnosis 4
1.3.2. Treatment 6
1.3.3. Resistant mechanisms to BRAF inhibitor in melanoma 7
1.3.4. Resistant mechanisms to immunotherapy in melanoma 9
1.4. microRNA 11
1.4.1. Introduction of miRNA 11
1.4.2. miR-524-5p 13
1.4.3. miR-567 14
1.5. Tumor microenvironment in melanoma 14
1.5.1. Tumor microenvironment in melanoma 14
1.5.2. Functions of miRNAs in tumor microenvironment. 16
1.6. Significances and purpose 18

Chapter 2 33
Materials and methods 33
2. 1. Human specimens 33
2. 2. Cell culture 33
2. 3. Construction of miR-567 inducible plasmid 34
2. 4. Construction of stable cells 34
2. 5. M1 and M2 differentiation 35
2. 6. Harvesting melanoma-conditioned media 35
2. 7. Melanoma-associated macrophages polarization 35
2. 8. Transfection 36
2. 9. Lentivirus infection 36
2. 10. Real-time quantitative PCR (RT-qPCR) 36
2. 11. In situ hybridization (ISH) and immunohistochemistry (IHC) 37
2. 12. Western blot 38
2. 13. AlamarBlue assay 38
2. 14. Colony formation assay 38
2. 15. Soft agar assay 39
2. 16. Wound healing assay 39
2. 17. Migration and invasion assays 39
2. 18. Cell cycle assay 40
2. 19. Bisulfite modification, methylation-specific PCR, and methylation-specific restriction endonucleases 40
2. 20. Xenograft 41
2. 21. Next-generation sequencing and ingenuity pathway analysis 41
2. 22. Statistical analysis 41
Chapter 3 42
miR-524-5p suppresses the development of BRAF inhibitor-resistant melanoma 42
3.1. Introduction 42
3.2. Results 43
3.2.1. miR-524-5p expression is involved in the response of melanoma patients to BRAF inhibitors 43
3.2.2. Novel pathways are related to resistance of BRAF inhibitor, PLX4032, in melanoma cells 43
3.2.3. miR-524-5p reduced the survival, anchorage-independent growth, migration, and invasion of BRAF inhibitor-resistant melanoma cells 44
3.2.4. miR-524-5p regulated the progression of BRAF inhibitor-resistant melanoma cells through multiple pathways 45
3.2.5. miR-524-5p reduces the tumor growth of BRAF inhibitor-resistant melanoma in vivo 46
3.3. Discussion 47
Chapter 4 63
Effects of miR-567 on the progression of melanoma and functions of macrophages 63
4.1. Introduction 63
4.2. Results 64
4.2.1. miR-567 expression decreases in melanoma 64
4.2.2. miR-567 suppresses the functions of melanoma 64
4.2.3. miR-567 reduced the growth of melanoma cells using an inducible system 65
4.2.4. miR-567 regulates the progression of melanoma cells through IGF1R, E2F1, and Cyclin B2 66
4.2.5. miR-567 modulates multiple pathways in melanoma cells. 67
4.2.6. Expression of miR-567 is related to response of melanoma patients to BRAF inhibitor 68
4.2.7. miR-567 reduced resistance to BRAF inhibitor in melanoma cells 69
4.2.8. M2 macrophages are increased in melanoma tissues 69
4.2.9. M1 and M2 macrophages are polarized from monocyte cells 70
4.2.10. Melanoma-associated macrophages are differentiated by melanoma-conditioned media 70
4.2.11. Conditioned media from M2 macrophages or MAMs induced the survival of melanoma cells 71
4.2.12. miR-567 reduced the function of M2 macrophages and melanoma-associated macrophages 72
4.3. Discussion 72
Chapter 5 101
Concluding remarks and future directions 101
5.1. Concluding remarks 101
5.2. Future directions 103
5.2.1. To explore the upstream regulators of miR-567 103
5.2.2. To explore the effects of miR-567 on the differentiation of melanoma-associated macrophages. 105
5.2.3. To investigate the functions of miR-567 in vivo 106
5.2.4. To investigate the functions of miR-567 in resistance to BRAF inhibitor in vitro and in vivo 107
References 129
Appendix A. The sequence or primers used in this study 143
Appendix B. Plasmid information 144
Appendix C. Publication list 145
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指導教授 馬念涵(Nianhan Ma) 審核日期 2022-7-25
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