以部分磷酸根甲基化改質去氧核醣核酸之寡核苷酸透過中孔洞二氧化矽奈米粒子增強細胞內miR-21抑制之研究

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蔡威霆(Wei-Ting Cai) 查詢紙本館藏

畢業系所

化學工程與材料工程學系

論文名稱

以部分磷酸根甲基化改質去氧核醣核酸之寡核苷酸透過中孔洞二氧化矽奈米粒子增強細胞內miR-21抑制之研究
(Enhanced Intracellular miR-21 Suppression via Partially Phosphate-methylated DNA Oligonucleic Acid Using Mesoporous Silica Nanoparticles)

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至系統瀏覽論文 (2026-8-1以後開放)

摘要(中)

微小RNA（microRNA, miRNA）是一種短小的非編碼RNA分子，其主要功能是在細胞內調控基因的表達。其中，miR-21在癌細胞中的高表達與促進細胞增殖、抑制細胞凋亡、促進侵襲和轉移等癌症相關特徵有很大的關聯性。因此針對miR-21的治療策略在癌症治療中具有重要意義。
為了有效抑制miR-21在癌細胞中的表達，本研究使用反義寡核苷酸（Antisense oligonucleotides, ASOs）作為癌細胞治療手段。反義寡核苷酸是一種透過靶向特定RNA序列來調控RNA表達的分子，然而，反義寡核苷酸存在的限制包括與其靶向RNA的結合力、在體內的分布和代謝以及易被酶分解等問題。因此，我們開發一種ASOs的類型，稱為中性化DNA（Neutralized DNA, nDNA），其磷酸骨架上含有位點特異性甲基磷酸三酯（Methyl phosphotriester, MPTE）鍵，將帶負電荷的DNA磷酸二酯轉變為中性化的MPTE，並且可以設計在任意位置。nDNA減少了磷酸骨架上的負電荷，從而減少了ASO與RNA雙鏈之間的靜電排斥力，這提高了雜交親和力和雙鏈穩定性。雖然nDNA以前已被作為靈敏核苷酸測序探針(Probe)應用於聚合酶連鎖反應(Polymerase chain reaction, PCR)中，可在DNA或RNA樣本中辨別和定量特定的核苷酸序列，但nDNA在細胞內對RNA的結合與調控和基因治療中的潛力仍然未被充分探索。本研究主要在評估nDNA作為ASO 在抑制細胞內miR-21基因表達及下游基因之調控能力。
在更具體的實驗設計中，本研究對nDNA進行了多種甲基化修飾，並評估了不同修飾位置對nDNA-ASO結合親和力和穩定性的影響。研究發現，當MPTE修飾位於N4-mid（修飾四個甲基在中間）位置時，nDNA對miR-21的抑制效果最佳，抑制持續時間也長達72小時。這表明精確定位的甲基化修飾不僅能提高nDNA的靶向能力，還能增強其在細胞內的穩定性。
本研究證明透過調整MPTE的位置，部分甲基化的nDNA裝載到中孔洞二氧化矽奈米粒子（Mesoporous Silica Nanoparticle, MSN）上，可以有效地抑制細胞內的miRNA表達，更可以進一步在結腸癌細胞HCT116中調控下游的信使核糖核酸（messenger RNA, mRNA）表達。此外，在72小時內裝載nDNA ASO的MSN在降低miR-21水平方面，比裝載未修飾的DNA ASO的MSN表現出更高的效力。相較於未修飾的DNA ASO，nDNA ASO也導致了下游腫瘤抑制基因PTEN和PDCD4的mRNA水平增加。
本研究發現，抑制miR-21後，下游的腫瘤抑制基因PDCD4和PTEN的mRNA表達顯著增強，這不僅抑制了腫瘤細胞的增殖，還促進了細胞的凋亡。本研究結果強調了nDNA在基因治療中的潛力，特別是透過精準調整甲基化位置來進行的癌症治療。這些結果顯示，nDNA不僅可以用於RNA調控，還能在癌症治療中發揮重要作用，提供了一種新的治療策略。
整體來說，本研究顯示了中性化DNA在細胞內RNA調控和基因治療中的巨大潛力，尤其在癌症治療中，透過精準調整甲基化位置，可以顯著提高治療效果。本研究為未來的體內實驗提供了強而有力的基礎，並為開發新型癌症治療方法提供了重要的理論支持。

摘要(英)

MicroRNAs (miRNAs) are short non-coding RNA molecules that play a crucial role in regulating gene expression within cells. miR-21 is highly expressed in cancer cells and is significantly associated with cancer-related characteristics such as promoting cell proliferation, inhibiting apoptosis, and enhancing invasion and metastasis. Therefore, therapeutic strategies targeting miR-21 hold great promise for cancer treatment.
To effectively suppress the expression of miR-21 in cancer cells, this study employs antisense oligonucleotides (ASOs) as a therapeutic approach. ASOs are molecules that regulate RNA expression by targeting specific RNA sequences. However, limitations of ASOs include their binding affinity to target RNA, distribution and metabolism within the body, and enzymatic degradation. To address these issues, we developed a type of ASO called neutralized DNA (nDNA), which incorporates site-specific methyl phosphotriester (MPTE) linkages on its phosphate backbone, converting the negatively charged DNA phosphodiester into a neutral MPTE at designated positions. The nDNA reduces the negative charge on the phosphate backbone, thereby decreasing electrostatic repulsion between the ASO and RNA duplex, enhancing hybridization affinity and duplex stability.
Although nDNA has previously been used as a sensitive nucleotide sequencing probe in polymerase chain reaction (PCR) to identify and quantify specific nucleotide sequences in DNA or RNA samples, its potential for binding and regulating RNA within cells and its role in gene therapy remain underexplored. This study focuses on evaluating the ability of nDNA as an ASO to inhibit miR-21 gene expression and regulate downstream genes within cells.
In more specific experimental designs, this study introduced various methylation modifications and assessed the impact of different modification sites on the binding affinity and stability of nDNA-ASO. The study found that when MPTE modification was in the middle position, nDNA exhibited optimal miR-21 inhibition, with the effect lasting up to 72 hours. This suggests that precise localization of methylation not only enhances the targeting capability of nDNA but also improves its stability within cells.
This study demonstrated that by adjusting the position of MPTE, partially and intermediately methylated nDNA loaded onto mesoporous silica nanoparticles (MSNs) effectively inhibited miRNA expression within cells and further regulated downstream messenger RNA (mRNA) expression in colon cancer cells (HCT116). Additionally, over 72 hours, nDNA ASO-loaded MSNs showed a greater reduction in miR-21 levels compared to unmodified DNA ASO-loaded MSNs. The miR-21 knockdown by nDNA ASO also resulted in increased mRNA levels of downstream tumor suppressor genes PTEN and PDCD4 compared to unmodified DNA ASO.
This study found that inhibiting miR-21 levels with nDNA ASO significantly enhanced the mRNA expression of downstream tumor suppressor genes PDCD4 and PTEN, indirectly suppressing cancer cell growth. These results highlight the potential of nDNA in cancer gene therapy, through precise methylation, indicating its role in RNA regulation, offering a new therapeutic strategy.
Overall, this study demonstrates the significant potential of nDNA in cancer gene therapy. Precise methylation can significantly improve RNA knockdown efficacy. This research provides a strong foundation for future in vivo experiments and offers an alternative strategy for gene cancer treatments.

關鍵字(中)

★ 反義寡核苷酸
★ 寡核苷酸修飾
★ 基因沉默

關鍵字(英)

★ antisense oligonucleotides
★ oligonucleotide modifications
★ gene silencing

論文目次

摘要 i
ABSTRACT iv
致謝 vi
目錄 viii
圖目錄 xii
表目錄 xvii
第一章緒論 1
第二章文獻回顧 5
2.1 癌症及基因突變 5
2.1.1 癌症概述 5
2.1.2 DNA突變及正常細胞癌變 8
2.2 基因沉默 11
2.2.1 在癌細胞中的蛋白表達 11
2.2.2 mRNA 轉譯機制 14
2.2.3 miRNA與基因調控 17
2.2.4 miR-21在癌細胞中的角色 20
2.2.5 在癌細胞中由miR-21調控的基因 22
2.3 反義寡核苷酸治療 25
2.3.1 反義寡核苷酸對基因調控 25
2.3.2 反義寡核苷酸的化學改質 29
2.3.3 Neutralized DNA (nDNA) 34
2.4 中孔洞二氧化矽奈米粒子 (MSN) 36
2.4.1 中孔洞二氧化矽奈米粒子簡介 36
2.4.2 功能化中孔洞二氧化矽奈米粒子 39
第三章實驗方法與儀器設備 41
3.1 實驗藥品 41
3.1.1 細胞培養 41
3.1.2 細胞轉染 41
3.1.3 核酸萃取 42
3.1.4 MSN和Probe-loaded MSN表徵 42
3.1.5 細胞毒性分析 42
3.1.6 釋放實驗 43
3.1.7 洋菜凝膠電泳(Agarose gel) 43
3.1.8模擬生物體內 miRNA 雜交 43
3.1.9 miRNA 逆轉錄反應 44
3.1.10 即時聚合酶鏈式反應 44
3.2 儀器設備 45
3.3 實驗方法 46
3.3.1細胞解凍 46
3.3.2 細胞培養 47
3.3.3 細胞冷凍 48
3.1.4 序列設計 49
3.3.5 MSN和Probe-loaded MSN表徵 50
3.3.6 細胞攝取 51
3.3.7 細胞毒性實驗 52
3.3.8 MSN 裝載效率 53
3.3.9 洋菜凝膠電泳(Agarose gel) 54
3.3.10 Probe-loaded MSN的血清穩定性 55
3.3.11 釋放實驗 56
3.1.12 模擬生物體內 miRNA 雜交 57
3.3.13 細胞萃取 59
3.1.14 逆轉錄及時聚合酶鍊式反應(qRT-PCR) 61
3.3.15 mRNA表達評估 67
第四章實驗結果與討論 68
4.1 在模擬人類血漿中 nDNA 對 miR-21 逆轉錄的抑制 68
4.2 中孔洞二氧化矽奈米粒子吸附能力研究 73
4.3 細胞攝取 76
4.4 MSN細胞毒性 79
4.5 ASO Probes在MSN-PEG/PEI中裝載效率 81
4.6 ASO-loaded MSN在血清中的穩定性 83
4.7 透過反義核酸探針抑制 HCT116 中的miR-21表達 85
4.8 PDCD4 和 PTEN mRNA 透過 miR-21 抑制在 HCT116 細胞中上調 89
4.9 癌細胞生長抑制 92
第五章結論 95
第六章未來展望 97
第七章參考文獻 98

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指導教授

陳文逸(Wen-Yih Chen)

審核日期

2024-7-4

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