探討DNA損傷反應與慢性暴露4-胺基聯苯產生之肝臟毒性;DNA Damage Response and Chronic Liver Toxicity Resulting from Exposure to 4-Aminobiphenyl

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题名:	探討DNA損傷反應與慢性暴露4-胺基聯苯產生之肝臟毒性;DNA Damage Response and Chronic Liver Toxicity Resulting from Exposure to 4-Aminobiphenyl
作者:	林衡道;Lin, Heng-Dao
贡献者:	生命科學系
关键词:	4-胺基聯苯;微小RNA;DNA修補;氧化壓力;肝細胞癌;斑馬魚;4-Aminobiphenyl;microRNA;DNA repair;oxidative stress;HCC;zebrafish
日期:	2021-01-20
上传时间:	2021-03-18 16:50:32 (UTC+8)
出版者:	國立中央大學
摘要:	4-胺基聯苯 (4-ABP)是一種人類膀胱致癌物，常見於偶氮染料及香菸、環境污染物產生的煙霧中。我們先前的研究發現4-ABP可在HepG2細胞誘導DNA損傷，顯示4-ABP可對人類肝細胞造成遺傳毒性。此外，流行病學調查也間接指出4-ABP可能對人類肝臟產生影響，但目前對於4-ABP是否對於人類肝臟產生致癌作用仍具有爭議。我們的目標是研究4-ABP短期高劑量暴露下產生的DNA損傷反應之分子機制以及長期低劑量暴露後是否可誘導肝癌產生。在第一部分，我們以L-02，HepG2和Hep3B等作為測試模型探討ROS及miRNA是否可參與4-ABP在人類肝細胞誘導的DNA損傷反應。實驗結果顯示高劑量4-ABP可誘導肝細胞產生ROS，並通過調節miR-513a-5p和miR-630的表現量進而抑制DNA同源重組修復活性。在第二部分中，我們利用人類肝細胞株和斑馬魚建立了肝細胞癌變模型，以模擬長期暴露於低劑量的4-ABP（1 nM-10 ?M）的肝癌發展。結果表明，低劑量4-ABP長期暴露可促進肝細胞增殖和遷移。此外， HBx, Src（p53-）轉基因斑馬魚暴露3個月4-ABP後及野生型斑馬魚中暴露6個月4-ABP都發現肝細胞癌形成。我們同時也發現細胞及斑馬魚模型中Ras-ERK途徑活化與4-ABP誘導的肝細胞癌之間的相關性。這些結果表明4-ABP可對肝臟產生遺傳毒性並促進肝細胞癌進展。據我們所知，這是首份關於慢性4-ABP暴露後促進人類細胞和斑馬魚產生肝癌之研究。;4-Aminobiphenyl (4-ABP) is a recognized human urinary bladder carcinogen that was commonly found in the manufacture of azo dyes, the compositions of cigarette smoke or polluted air. In our previous study, we found 4-ABP can induce DNA damage in HepG2 cells. Many epidemiologic studies have investigated the potential effects of 4-ABP on liver, but the oncogenic effect of 4-ABP on human liver remains controversial. Our purpose is to investigate the molecular mechanism of DNA damage response after acute 4-ABP treatment and whether 4-ABP induced liver carcinogenesis after chronic exposure. In the first part of our studies, we used human liver cells like L-02, HepG2 and Hep3B as a test model to investigate whether the ROS and miRNA affect DNA damage response during exposure to various concentrations of 4-ABP (75-300 ?M) for 24 h. Our results showed that 4-ABP induces ROS production which inhibiting DNA homologous recombination (HR) repair activity via regulated miR-513a-5p and miR-630 expression. In the second part, we have established a liver cell carcinogenesis model in human liver cell lines and zebrafish to mimic liver cancer development associated with long-term exposure to low doses of 4-ABP (1 nM-10 ?M). The results demonstrated that chronic 4-ABP exposure promoted cellular proliferation and migration in vitro. In addition, 4-ABP induces hepatocellular carcinoma (HCC) formation in HBx, Src (p53-) transgenic zebrafish at four months of age and in wild-type zebrafish at seven months of age. We also observed a correlation between the Ras-ERK pathway and 4-ABP-induced HCC in vitro and in vivo. These results indicated that 4-ABP has effects on genotoxicity in liver and HCC progression. To our knowledge, this is the first report on the promotion of liver carcinogenesis in human cells and zebrafish following 4-ABP exposure.
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