4-Aminobiphenyl 調控 miR-630 抑制 RAD18 表現誘導 Hep3B 細胞產生氧化性 DNA 損傷

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王方宗(Fang-Zong Wang) 查詢紙本館藏

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論文名稱

4-Aminobiphenyl 調控 miR-630 抑制 RAD18 表現誘導 Hep3B 細胞產生氧化性 DNA 損傷
(The microRNA-630 is involved in oxidative DNA damage in 4-aminobiphenyl-treated Hep3B cells via downregulation RAD18)

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摘要(中)

4-胺基聯苯(4-aminobiphenyl；4-ABP)為多環芳香族的聯苯胺衍生物，在燃燒的香菸與汽車排放的煙霧中發現大量4-ABP 化合物，4-ABP進入到人體後，會藉由肝臟細胞的phase I與phase II的氧化還原進行代謝，解毒過程會產生自由基，進一步地導致DNA 損傷。4-ABP 15分鐘生成ROS，Comet assay 24小時後會導致Hep3B Cells 發生DNA 損傷，且 -H2AX (DNA double stand break sensor protein) 表現增加，RAD18 表現降低。再者，已知4-ABP 可誘導 HepG2 cells 產生多種 miRNA，尤其以 miR-513a-5p 和 miR-630 表現量最顯著。因此，本篇研究將探討4-ABP造成氧化型DNA損傷，是否透過miR-513a-5p 和 miR-630的調控。利用生物資訊軟體TargetScan 7.1預測此二miRNA 之標的基因，可能為RAD18、FANCG及XRCC2，由qRT-PCR 證實在HepG2與Hep3B細胞中只有miR-630 大量表現，且確認RAD18 轉譯會受到miR-630的直接調控。大量表現miR-630 導致RAD18 表現降低。4-ABP 與N-acetyl-L-cysteine (NAC)(一種自由基抑制劑) 合併處理會抑制ROS的產生，miR-630 表現也隨之降低，故得知miR-630 為ROS dependent miRNA。大量表現RAD18後，細胞核中 -H2AX foci聚集顯著降低，4-ABP造成homologous recombination 效率降低，此外，4-ABP抑制RAD18後也會使RAD51 (homologous recombination repair protein)表現降低。本研究發現了4-ABP造成基因毒性是透過ROS-dependent miR-630 活化，抑制RAD18，接著降低 Homologous Recombination活性，導致損傷之DNA 無法修復。
本研究首次證實4-ABP可造成肝臟細胞的氧化基因損傷之其中一種 ROS-dependent miRNA 機制。

摘要(英)

4-aminobiphenyl (4-ABP) is a well-recognized human carcinogen, and has been found in textile dyes, cooking oil fumes, diesel-exhaust particles and cigarette smoke. 4-ABP induces oxidative stress and DNA damage that are associated with hepatic gene toxicity. My research foused on the role of miRNA-630 on RAD18, a DNA-repair protein. Firstly, 4-ABP induced ROS generation and DNA damage in Hep3B cells. The amount of 4-ABP-induced DNA double strand breaks (DSB) in a concentration- and time-dependent by determining the expression of -H2AX (the biomarker of DSB) with the methods of Western blot and Immunofluorescence staining assay. Luciferase reporter assay further confirmed miR-630 specifically targeted the 3’UTR of RAD18; thereby inhibiting RAD18 gene expression. Pretreatment of 4-ABP-treated cells with 5 mM N-acetyl-I-cysteine (NAC) attenuated the levels of miR-630 suggest that miR-630 was a ROS- dependent miRNA in 4-ABP-treated cells. 4-ABP treatment also inhibited the activity of DNA double stand break repair. This study showed that 4-ABP induces ROS generation in Hep3B cell line, and then increased the expression of the oxidative stress response-associated with the involvement of miR-630 in DNA damage. Elevated miR-630 expression inhibits RAD18 expression, with subsequent inhibition of homologous recombination.

關鍵字(中)

★ 對胺基聯苯
★ 氧化壓力
★ miR-630
★ DNA 損傷
★ DNA 修復
★ 同源重組

關鍵字(英)

★ 4-Aminobiphenyl
★ Oxidative stress
★ miR-630
★ DNA damage
★ DNA repair
★ Homologous Recombination

論文目次

目錄
中文摘要 I
Abstract II
目錄 III
圖目錄 VI
表目錄 VII
第壹章、緒論 1
一、 4-胺基聯苯 (4-aminobiphenyl，4-ABP) 1
(一) 偶氮染料 1
(二) 菸草燃燒煙霧 2
(三) 4-ABP 經由肝臟代謝後之代謝產物與DNA adducts 之形成 3
二、氧化壓力 (Oxidative stress) 4
(一) 自由基的分類 5
(二) 抗自由基的機制 6
(三) 氧化壓力造成DNA damage 7
三、基因毒性反應 (DNA damage response; DDR) 7
四、 DNA 修復(DNA Repair) 8
五、表觀遺傳調控(Epigenetic) 10
(一) DNA甲基化 (DNA methylation) 11
(二) 組蛋白修飾 (histone modification) 11
(三) RNA干擾 (RNA interference) 11
六、微型核醣核酸(microRNA;miRNA) 12
(一) miRNA 的介紹 12
(二) miRNA 的發現 13
(三) miRNA 的生成 13
(四) miRNA在mRNA的調控機制與結合方式 15
(五) miRNA 基因的辨識與預測 16
第貳章、實驗目的與架構 18
第參章、實驗材料與方法 19
一、細胞株來源及細胞培養 19
二、細胞計數與存活測試 21
三、化學物質處理 22
四、細胞存活率分析(MTT assay) 22
五、細胞內活性氧化物質測定 23
六、 DNA損傷測定-彗星試驗(Comet assay) 25
七、蛋白質萃取 28
八、蛋白質定量 29
九、蛋白質樣品處理 30
十、蛋白質電泳 31
十一、蛋白質轉漬 33
十二、西方墨點法 34
十三、哺乳類細胞RNA萃取(RNA Isolation) 36
十四、 mRNA 反轉錄成cDNA 38
十五、 DNA/RNA 電泳 40
十六、 miRNA 萃取(miRNA Isolation) 41
十七、 miRNA 反轉錄為cDNA 43
十八、即時定量聚合酶連鎖反應 45
十九、大腸桿菌勝任細胞之製備 47
二十、大腸桿菌勝任細胞之轉型作用 48
二十一、利用限制酵素切開雙股DNA 49
二十二、插入子與載體接合與酒精沉澱DNA 50
二十三、質體抽取(Plasmid DNA Isolation) 51
二十四、質體純化－去除內毒素 52
二十五、定點突變(Site Directed Mutation，SDM) 53
二十六、質體及oligo RNA 轉染(Transfection) 55
二十七、螢光酶活性測試 56
二十八、免疫螢光染色(Immunofluorescence staining) 57
二十九、同源重組活性測試 60
第肆章、結果 (Result) 62
一、評估4-胺基聯苯(4-ABP)對於Hep-3B 與 Hep-G2 cell 之細胞毒性影響 62
二、評估4-胺基聯苯(4-ABP)對於Hep-3B 與 Hep-G2 cell 誘導氧化壓力和DNA損傷程度 63
三、利用qRT-PCR 分析miR-513a-5p 與miR-630的表現 64
四、利用qRT-PCR 與Western Blot 分析4-ABP 誘導之RAD18 mRNA 及蛋白質表現 64
五、利用預測軟體分析其miRNA target interaction binding site 65
六、觀察Luciferase之螢光活性，探討miR-630是否會target在RAD18之3’-UTR 65
七、利用miR-630 mimic and inhibitor，探討與RAD18 之間的關係 66
八、探討ROS 是否為誘導miR-630上升的主因 67
九、 4-ABP 產生ROS誘導DNA damage 及調控DNA repair protein RAD18 之影響 67
十、探討RAD18 在 4-ABP 處理細胞後產生DNA repair 所扮演得角色 69
十一、測定RAD18 於Homologous Recombination 之活性. 70
第伍章、討論 71
一、細胞株的選取 71
二、探討4-ABP對於肝臟細胞之基因毒性機制 72
三、探討DNA 損傷啟動DNA Response機制 73
四、從表觀遺傳學之角度探討基因變化 74
五、探討4-ABP誘導ROS的生成及經由表觀遺傳調控DNA Response 之DNA Repair 76
六、 miR-630 扮演的角色為何? 77
七、 RAD18 在4-ABP 造成雙股斷裂中進行DNA 修復的角色 78
第陸章、結論 79
第柒章、圖表 80
第捌章、參考文獻 108
第玖章、附錄 116

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指導教授

陳師慶(Ssu-Ching Chen)

審核日期

2017-6-15

推文