探討化合物 Y 抑制神經母細胞瘤增生之效果

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賴政秀(Jheng-Siou Lai) 查詢紙本館藏

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探討化合物 Y 抑制神經母細胞瘤增生之效果
(Investigating the Proliferation-Inhibiting Effects of Compound Y on Neuroblastoma)

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★ 探討化合物Y抑制神經母細胞瘤轉移之效果

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摘要(中)

神經母細胞瘤是兒童常見的顱外實體瘤，起源於交感神經系統，好發於腹腔之神經節及腎上腺。經過幾十年來的研究，即使採用最先進的治療方法，高危族群的神經母細胞瘤患者的生存率仍舊低於50%。這顯示現有藥物不足以有效治愈患者，因此，開發治療神經母細胞瘤的新藥是迫切需要的。根據我們的先前研究發現芳香烴接受器（AHR）的表達與神經母細胞瘤的分化程度呈高度正相關。當AHR被大量表達時可以抑制神經母細胞瘤細胞增殖並促進其分化。此外，AHR受到配體激活時，亦可達到與大量表達AHR的相似治療效果，顯示AHR配體具有開發成神經母細胞瘤治療藥物之潛力。因此，在本研究中我想研究AHR的新型配體 compound Y是否對NB具有增殖抑製的作用。研究結果發現，以 compound Y處理SK-N-BE 以及 SK-N-SH神經母細胞瘤細胞後，透過細胞計數實驗可以觀察到細胞數在高濃度compound Y處理的組別顯著降低。透過MTS分析的結果也呈現相似的結果，compound Y有效降低細胞活性，顯示細胞增殖受到抑制。除此之外，於細胞聚落生成實驗中也可以觀察到高濃度 compound Y 會使細胞聚落生成降低。透過細胞週期分析亦發現compound Y促使細胞停滯在G0/G1期的比例上升。另一方面，由於先前研究指出，AHR訊息路徑的活化有助於神經母細胞瘤之分化，此研究也藉由觀察細胞分化型態的改變以及分化標誌TUJ1、NSE及NF-H的mRNA表現來確定compound Y 的促分化能力。最後，透過 Annexin V-FITC染色初步證實compound Y也具有促進神經母細胞瘤細胞凋亡之特性。總結來說，本研究利用多種研究方式證實了AHR的新型配體 compound Y確實具有抑制神經母細胞瘤生長之功效。

摘要(英)

Neuroblastoma (NB) is the most common extracranial solid tumor in children, which originates from the sympathetic nervous system and is more likely to occur in the ganglion of the abdominal cavity and the adrenal gland. After decades of investigation, the survival rate of high-risk NB patients is still less than 50%, even with advanced therapies. This indicates that existing drugs are not effective enough to cure patients, therefore, the development of new drugs to treat NB is urgently needed. Our previous study found that the expression of aryl hydrocarbon receptor (AHR) was positively correlated with the differentiation histology of NB tumors. AHR overexpression can inhibit the proliferation of NB cells by promoting their differentiation. In addition, AHR activation by a ligand can also achieve a similar therapeutic effect to that of AHR overexpression, indicating that AHR ligands have therapeutic potential for NB. Therefore, in this study, I would like to investigate whether compound Y, a novel ligand of AHR, has a proliferation-inhibiting effect on NB. To this end, SK-N-BE and SK-N-SH NB cells were treated with compound Y. By the cell counting experiments, I found that the number of cells in the group treated with high concentrations of compound Y was significantly reduced. The results of MTS analysis also showed similar results, compound Y effectively reduced cell viability, showing that cell proliferation was inhibited. In addition, in the colony formation assay, it can also be observed that a high concentration of compound Y reduced the cell colony formation. Cell cycle analysis also found that compound Y induces cell arrest in G0/G1 phase. On the other hand, since previous studies have pointed out that the activation of AHR signaling pathways contributes to NB′s differentiation, compound Y′s effects in promoting cell differentiation were observed in this study. By observing the morphology change and the mRNA expression of differentiation markers TUJ1, NSE, and NF-H, I suggest that compound Y has the ability to induce differentiation of NB cells. Lastly, through Annexin V-FITC staining, it was preliminarily confirmed that compound Y also has the property of promoting apoptosis of NB cells. In conclusion, this study has confirmed that compound Y inhibits the proliferation of NB by using various research methods.

關鍵字(中)

★ 神經母細胞瘤
★ 芳香烴接受器

關鍵字(英)

★ Neuroblastoma
★ AHR

論文目次

第⼀章、緒論 p.1
1-1 兒童癌症 p.1
1-1-1 成因與特色 p.2
1-1-2 治療 p.3
1-2 神經⺟細胞瘤 p.4
1-2-1 患者統計 p.4
1-2-2 診斷方法 p.5
1-2-3 腫瘤分布與病況 p.5
1-2-4 臨床表現與分期判定 p.6
1-2-5 ⾵險與⽣物學上的特異性 p.7
1-3 MYCN 與神經母細胞瘤 p.8
1-3-1 在神經母細胞瘤中的調節 p.8
1-3-2 MYCN對細胞增殖與細胞週期的影響 p.9
1-3-3 MYCN對細胞凋亡的影響 p.10
1-4 芳香烴接受器 p.11
1-4-1 AHR的作用機制 p.11
1-4-2 配體激活AHR可促進細胞增殖 p.12
1-4-3 配體激活AHR可抑制細胞增殖 p.12
1-4-4 藥物開發-AHR內源性配體 p.13
1-5 3α.5α-四氫皮質酮(5α-THB)和3α.5β-四氫皮質酮(5β-THB) p.14
1-5-1 5α-THB的抗炎功能 p.15
1-5-2 5α-和5β-THB在神經細胞的功能 p.15
1-5-3 5α-THB和5β-THB的異構物compound Y p.17
1-6 研究動機和⽬標 p.18
第二章、材料與方法 p.19
2-1 細胞培養 p.19
2-2 藥劑和試劑配置 p.19
2-3 西方墨點法 p.19
2-4 細胞計數 p.20
2-5 MTS分析 p.20
2-6 流式細胞儀分析 p.21
2-6-1 Cell cycle分析檢測細胞增生 p.21
2-6-2 Annexin V-FITC染⾊檢測細胞凋亡 P.21
2-7 RNA反轉錄成cDNA p.21
2-8 即時聚合酶連鎖反應(SYBR Green Real-Time PCR) p.22
2-9 細胞群落形成分析 p.22
第三章、實驗結果 p.24
3-1 Compound 在神經⺟細胞瘤中對細胞增生的影響 p.24
3-1-2 神經⺟細胞腫瘤細胞處理Compound Y細胞代謝活性被抑制 p.25
3-1-3 神經⺟細胞瘤細胞處理Compound Y後細胞群落⽣成被抑制 P.26
3-1-4 神經⺟細胞瘤細胞處理Compound Y後細胞停留在G0/G1期 p.27
3-2 Compound Y在神經⺟細胞瘤中對細胞分化的影響 P.27
3-3 Compound Y在神經⺟細胞瘤中對細胞凋亡的影響 p.28
第四章、討論 p.30
第五章、參考⽂獻 p.41

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指導教授

吳沛翊(Pei-Yi Wu)

審核日期

2023-8-17

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