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研究生:胡鈺杰
研究生(外文):Yu-Jie Hu
論文名稱:單甲基亞砷酸長期暴露導致人類膀胱泌尿道上皮細胞株的細胞轉型與基因異常表現之探討
論文名稱(外文):Transformation Phenotype and Aberrant Gene Expression Induced by Long-term Exposure of Monomethylarsonous Acid in Human Urothelial Cell Line
指導教授:李德章李德章引用關係
指導教授(外文):Te-Chang Lee
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生物藥學研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
中文關鍵詞:單甲基亞砷酸膀胱上皮細胞
外文關鍵詞:arsenicmonomethylarsonous acidurothelial cell
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砷為公認之人類致癌物。許多流行病學的研究顯示,砷污染地區居民罹患膀胱泌尿道上皮細胞癌(urothelial carcinoma)的發生率與死亡率都顯著較高,但尿液中的砷化物是否為造成膀胱泌尿道上皮細胞癌化的主因與其致癌機轉為何,目前尚不清楚。近年來發現砷的三價甲基化代謝產物存在於砷暴露地區居民的尿液中,其中monomethylarsonous acid (MMAⅢ)的細胞與遺傳毒性較三價無機砷高,並且具有抑制酵素、改變基因轉錄、刺激細胞分泌生長因子及細胞激素等作用,因此MMAⅢ在砷的毒性與致癌機轉中可能扮演重要的角色。本研究即利用無腫瘤生成能力(non-tumorigenic)的人類泌尿道上皮細胞株(SV-HUC-1),以低濃度(0.05~0.2 □M) MMAⅢ長期處理,探討MMAⅢ的長期暴露是否導致細胞惡性轉型(malignant transformation)及其可能的致癌機轉。
  
經過MMAⅢ的長期處理(>20 passages),建立四株長期培養的細胞株(M0、M0.05、M0.1、M0.2)。MMAⅢ的長期處理造成包括細胞型態明顯的改變、於無血清培養下能持續存活與生長、在軟洋菜膠上非固著性生長(anchorage-independent growth)能力的增加、細胞間的裂隙結合(gap junction intercellular communication)的降低等現象,顯示MMAⅢ具有腫瘤促進物(tumor promoter)的特性。將MMAⅢ長期處理之細胞植入裸鼠(nude mice)皮下,經4個月仍無法形成腫瘤,顯示細胞尚未具有腫瘤生成能力。此外本研究以cDNA微陣列(cDNA microarray)的技術對於MMAⅢ長期處理之細胞的基因表現模式(gene expression profile)進行分析,並篩選出12個有顯著差異表現的基因後,以Gene Ontology進行基因的歸類,約有50 %的基因與生長調控及訊號傳遞有關。上述篩選出的基因進一步以同步定量PCR (real-time PCR)進行基因表現量之確認。其中Heparin-binding EGF like growth factor (HB-EGF)在MMAⅢ長期處理後基因表現量顯著上升,其蛋白質的功能可藉由結合於EGF receptor上並活化下游訊息傳遞而促進細胞生長與存活,本研究利用西方點墨法與免疫螢光染色法確認該蛋白質表現,並以免疫組織染色法於人類膀胱癌組織中驗證。綜合以上結果,低劑量MMAⅢ長期處理雖尚未使無腫瘤生成能力之細胞轉變為具腫瘤生成能力的細胞,但基因的異常表現與細胞存活和生長特性的改變顯示細胞已具有轉型的特徵。
Arsenic is classified as a human carcinogen. Numerous epidemiological studies demonstrated a significant association between ingested arsenic and increased risk of urothelial carcinoma in arseniasis endemic area, however it is still unclear whether human urothelial cells are directly susceptible to urinary arsenicals-induced malignant transformation. Among the metabolites of ingested inorganic arsenic (iAs), monomethylarsonous acid (MMAⅢ) has been shown to be equal or more potent in cytotoxicity, genotoxcicity, enzymes inhibition, altered gene transcription, stimulated growth factors and cytokines secretion. In this study, we evaluated the carcinogenicity of MMAⅢ that was suspected to play an important role in arsenic carcinogenesis of urinary bladder.

The long-term treated cell lines were established by exposing continuously of non-tumorigenic human urothelial cells (SV-HUC-1) to low concentrations (0.05, 0.1, and 0.2 μM) of MMAⅢ over 20 passages. As compared with untreated control cells, long-term treated cells revealed the morphological changes, prolonged survival and continuous proliferation in serum-free medium, enhanced anchorage-independent growth and reduced the gap junction intercellular communications. However, tumors were not formed 4~5 months after subcutaneous injection of long-term treated cells into nude mice. Gene expression profiles of long-term treated cells were generated by cDNA microarray and further confirmed by real-time PCR. By the aid of Gene Ontology tools, half of significant changed genes were classified in growth control and signal transduction. In addition, enhanced protein expression of heparin-binding EGF like growth factor (HB-EGF), an EGFR ligand and a potent mitogen, were detected in long-term treated cells and in urothelial carcinoma specimens. In conclusion, low concentration and long-term MMAⅢ treatment cause aberrant gene expression and transformation of human urothelial cells, but they remain non-tumorigenic.
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