4-胺基聯苯(4-ABP)為人類的致癌物質，主要引起膀胱癌；肝癌，乳癌等。2-胺基 聯苯(2-ABP)為其同分異構物。在彗星試驗的結果已經證明兩者會對HepG2 細胞 DNA 造成氧化性傷害。DNA 損傷的訊息傳遞結果包含細胞凋亡，DNA 修補酵素活化和 細胞週期停滯等。用microarray 分析初步結果發現2-胺基聯苯和4-胺基聯苯對人類肝 臟細胞(HepG2 cells) 功能性基因表現之profiles 可能完全不同。第一年本計劃探 討2-ABP 和4-ABP 對人類肝臟細胞和膀胱癌細胞產生DNA 訊息傳遞途徑是否有何不 同? DNA damage signaling 可被ATM (ataxia telangiectasia mutated) 和ATR (ataxia telangiectasia related) protein kinases 啟動，這些kinases 可被不同型式之DNA damage 所活化. 這些kinases 被活化後，可作用在多種蛋白質如細胞產生cell cycle arrest 後， 多種DNA repair pathways 可分別對一些特定DNA damage 型式進行修補，阻止DNA damage 細胞進行增殖。第二年探討2-ABP and 4-ABP 產生DNA damage signaling pathways 包含ATM/ATR protein kinases 活化導致p53 and chk2 磷酸化產生cell cycle arrest 可能性，並探討多種DNA repair enzymes 酵素參與可能性。 已有65 mi RNAs 在cancer-associated pathways 如transcription ， cell-cell adhesion and signaling，cell-cycle regulation，cell proliferation and apoptosis 扮演重要角 色。2-ABP and 4-ABP- treated cells 是否可能產生mi RNA profiles 改變，或mi RNA 可 參與apoptosis 調控，並不清楚? 因此，第三年研究目的探?mi RNA 參與DNA damage response 的調控扮演之角色。4-Aminobiphenyl (4-ABP), a carcinogen, can induce the bladder cancer, liver cancer, and breast cancer. 2-aminobipheny (2-ABP) is an isomer of 4-ABP. Both compounds can cause the oxidative DNA damage in the Hep G2 cells. The DNA damage signaling pathways include the apoptosis, the cell cycle arrest, and the DNA repair pathway. Preliminary data revealed that the profiles of the expression of functional genes are distinct between in 2-ABP-treated Hep G2 cells and 4-ABP-treated cells. The DNA damage signaling pathways in both compounds-treated Hep G2 cells and bladder cancer cells were compared, to delineate the molecular mechanism of genotoxicity in both kinds of cells. The DNA damage signaling pathways can be induced by ATM and ATR, a protein kinase. These protein kinases can activate across other signaling pathways; for example, inducing the DNA repair pathway when cells’ encounteringthe cell cycle arrest. The activation of DNA repair pathway can prevent the DNA damage cells from proliferation leading to carcinogenesis. It is likely that the activation of ATM and ATR in controlling the downstream proteins such as phosphorylation of p53 and chk2 results in cell cycle arrest, which can enable the DNA repair proteins to repair these DNA damage cells. Whether 2-ABP and 4-aBP-treated cells can trigger the activation of protein kinases remains unknown. Thus, we will focus on the roles of protein kinase in DNA damage –induced by both compounds. At least 65 kinds of miRNAs play a role in cancer-associated pathways such as transcription, cell-cell adhesion and signaling, cell-cycle regulation, cell proliferation and apoptosis. Both the changes of miRNA in both compounds-treated cells and the role of miRNA in DNA damage will be addresses; after all, the study of application of miRNA in toxicology is scarce.研究期間：10108 ~ 10207
