探討硒代胱氨酸於神經母細胞瘤之治療潛力

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曾桾溦(Chun-Wei Tseng) 查詢紙本館藏

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論文名稱

探討硒代胱氨酸於神經母細胞瘤之治療潛力
(The Therapeutic Potential of Selenocystine in Neuroblastoma)

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至系統瀏覽論文 (2026-8-31以後開放)

摘要(中)

神經母細胞瘤（Neuroblastoma, NB）是一種源於交感神經系統胚胎神經嵴細胞的神經癌症，是兒童中最常見的顱外固體腫瘤。高風險患者通常高機率會有低生存率和不良的預後的狀況發生，因此想要提升高風險群體的存活率，開發有效的抗癌藥物是迫切需要的。硒代胱氨酸（Selenocystine, SeC）作為一種含硒氨基酸，已被許多先前的研究證實它是一個有抗腫瘤治療前景的候選藥物。更重要的是，SeC能夠選擇性地靶向癌細胞，而不對正常細胞造成損害。儘管在多種癌症類型中已經說明了SeC的抗增殖效應和其很適合做為抗癌藥物的選擇性，但SeC在NB中的治療潛力仍然鮮有研究。本研究旨在使用SK-N-BE(2)C和SK-N-SH細胞作為體外模型，探討SeC作為NB治療劑的功效。細胞計數、MTS試驗和聚落形成試驗顯示，SeC處理後細胞存活率呈劑量依賴性下降，突顯了其對NB的抗增殖效應。進一步使用流式細胞儀分析表明，SeC誘導細胞在Sub-G1期的積聚和Annexin V陽性細胞增加，表明細胞凋亡的發生。不論是對於凋亡相關的蛋白質標記如PARP、Caspase 3、Caspase 8和Bcl-2，還是對於凋亡相關的基因標記表達水平如Bcl-2和Bax，均顯示出明顯的凋亡效應。為了闡明其潛在機制，我們在SeC處理的SK-N-BE(2)C細胞中進行了RNA-Seq分析。從生物學過程（Biological Process, BP）和疾病本體（Disease Ontology, DO）的超表達分析中可以明顯看出，許多與神經功能相關的基因發生了改變。這進一步證實了SeC對NB細胞具有很大的影響。從Volcano Plot可以看出KLF4和CDKN1A基因明顯上調，顯示SeC誘導的細胞週期阻滯和細胞凋亡可能通過KLF4-CDKN1A途徑進行調節。隨後的研究將探討KLF4和CDKN1A在SeC誘導的NB細胞反應中的具體作用。除此之外，將進行體內腫瘤異種移植研究，以進一步驗證SeC在更貼近生理情況下的治療潛力。

摘要(英)

Neuroblastoma (NB) is a neural cancer originating from embryonic neural crest cells of the sympathetic nervous system. It represents the most prevalent extracranial solid tumor in children, and patients classified as high-risk typically face a poor prognosis with low survival rates. Developing an effective anti-tumor drug for high-risk patients is urgent for the current NB treatment. Selenocystine (SeC), a selenium-containing amino acid, has emerged as a promising candidate for anti-tumor therapy in several previous studies. Importantly, SeC can selectively target cancer cells while sparing normal cells from harm. Despite the documented anti-proliferative effects and the advantageous characteristic of SeC across various cancer types, its therapeutic potential in NB remains largely unexplored. In this study, we aim to investigate the efficacy of SeC as a therapeutic agent for NB using SK-N-BE(2)C and SK-N-SH cells as in-vitro models. Cell counting, MTS assays, and colony formation assays revealed a dose-dependent reduction in cell viability following SeC treatment, underscoring its anti-proliferative effects in NB. Further analysis using flow cytometry demonstrated SeC-induced accumulation of cells in the sub-G1 phase and an increase in Annexin V-positive cells, indicative of apoptosis. Regardless of the protein markers of apoptosis such as PARP, Caspase 3, Caspase 8, and Bcl-2, or the mRNAs expression levels of apoptosis-related genes such as Bcl-2 and Bax, both of them showed significant apoptosis induced by SeC. To elucidate the underlying mechanisms, RNA-Seq analysis was employed in SeC-treated SK-N-BE(2)C cells. From the over-representation analysis of Biological Process (BP) and Disease Ontology (DO), it is evident that numerous genes related to neural functions are altered. This further confirms that SeC has a huge impact on NB cells. The volcano plot revealed significant upregulation of the KLF4 and CDKN1A genes, indicating that SeC-induced cell cycle arrest and apoptosis in NB cells may be mediated by the KLF4-CDKN1A pathway. Subsequent studies will explore the specific roles of KLF4 and CDKN1A in SeC-induced responses in NB cells. Additionally, an in-vivo xenograft study will be conducted to validate the therapeutic potential of SeC in a more physiological setting.

關鍵字(中)

★ 神經母細胞瘤
★ 硒代胱氨酸

關鍵字(英)

★ Neuroblastoma
★ Selenocystine

論文目次

誌謝 i
中文摘要 ii
Abstract iii
Table of Contents v
List of Figures ix
List of Tables x
Chapter 1. Introduction - 1 -
1-1 Basic information of neuroblastoma - 1 -
1-1-1 Neuroblastoma - 1 -
1-1-2 MYCN is an important biomarker of NB - 2 -
1-2 Roles of KLF4 in neuroblastoma - 2 -
1-2-1 Characteristics of KLF4 - 3 -
1-2-2 Functions in KLF4 in cancers - 3 -
1-2-3 KLF4 signaling pathways in tumors - 4 -
1-2-4 KLF4 might be a tumor suppressor in NB - 5 -
1-3 Roles of CDKN1A in neuroblastoma - 6 -
1-3-1 Characteristics of CDKN1A - 6 -
1-3-2 Functions in CDKN1A in cancers - 6 -
1-3-3 CDKN1A might be a tumor suppressor in NB - 7 -
1-3-4 The connection between KLF4 and CDKN1A in NB - 8 -
1-4 Selenocystine (SeC) - 8 -
1-4-1 The function of selenium in the human - 8 -
1-4-2 Anticancer activities of selenocompounds - 8 -
1-4-3 Characteristic of Selenocystine in cancer cell - 9 -
1-5 Rationale - 11 -
1-6 Research framework - 12 -
Chapter 2. Materials & Methods - 13 -
2-1 Cell lines & medicament - 13 -
2-2 Cell culture - 13 -
2-3 MTS assay - 13 -
2-4 Cell counting - 14 -
2-5 qPCR - 15 -
2-5-1 RNA extraction - 15 -
2-5-2 Reverse transcription PCR (RT-PCR) - 16 -
2-5-3 Quantitate real-time PCR (qRT-PCR) - 16 -
2-6 Western blot - 17 -
2-6-1 Protein extraction - 17 -
2-6-2 SDS-polyacrylamide gel electrophoresis, SDS-PAGE - 17 -
2-6-3 Transfer - 18 -
2-6-4 Blocking and antibody recognition - 18 -
2-6-5 Stripping - 18 -
2-7 Flow cytometry - 19 -
2-7-1 Cell apoptosis assay - 19 -
2-7-2 Cell cycle distribution analysis - 19 -
2-8 Colony formation - 20 -
2-9 RNA-sequencing - 21 -
2-9-1 RNA QC - 21 -
2-9-2 Library Preparation and Sequencing - 21 -
2-9-3 Differential Expression Analysis - 21 -
2-9-4 Enrichment Analysis - 22 -
2-10 Statistical analysis - 22 -
Chapter 3. Results - 23 -
3-1 SeC inhibits the cell proliferation of NB cells - 23 -
3-2 SeC downregulates PCNA protein expression level and mRNA expression in NB cell lines - 24 -
3-3 SeC promotes the accumulation of NB cells in Sub-G1 phase - 24 -
3-4 SeC induces apoptosis of NB cells - 24 -
3-5 RNA sequencing analysis demonstrates the induction of KLF4 and CDKN1A in SeC-treated NB cells - 25 -
Chapter 4. Discussions & Conclusion - 27 -
Chapter 5. References - 32 -
Chapter 6. Appendixes - 63 -

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指導教授

吳沛翊(Pei-Yi Wu)

審核日期

2024-8-22

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