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標題: | 肝臟癌變過程NRF2經由活化癌症相關的訊息途徑促進細胞增生和轉移 NRF2 accelerates cell proliferation and metastasis through activation of cancer-associated signaling cascades during liver carcinogenesis |
作者: | Shu-Yuan Mai 麥淑媛 |
指導教授: | 鄭永銘 |
關鍵字: | 肝細胞癌,NRF2,KEAP1,c-Fos,EID3,肝臟癌變, Hepatocellular carcinoma (HCC),NRF2,KEAP1,c-Fos,EID3,liver carcinogenesis, |
出版年 : | 2015 |
學位: | 碩士 |
摘要: | 肝細胞癌是肝癌的最常見的類型,現在是全世界癌症死亡的第二大原因。根據最近外顯子組定序研究,許多突變基因和訊息途徑與肝細胞癌的生成有關。最常突變的基因包括TERT(59%)、beta-catenin(10〜32%)、TP53(18〜35%)、MLL(17〜20%)、JAK1(9%)、KEAP1(8%)和NRF2(6%)。在肝細胞癌中NRF2的突變和異常堆積,在肝臟癌變過程中可能扮演促進惡性細胞生長的重要角色。NRF2執行細胞防禦的功能來抵抗氧化和親電子所造成的壓力並且保護細胞免受於化學性的癌變發生。然而,最近的許多研究發現,許多種癌症有NRF2蛋白質異常堆積和活化的現象。在此研究中,我們探討NRF2如何促進肝臟癌變。我們的研究發現,使用核糖核酸干擾(RNA interference)抑制NRF2的表現量在體外培養實驗和體內小鼠異種移植實驗中會抑制細胞增生、聚球(sphere formation)能力、移動和侵犯的能力。我們通過微陣列分析結果發現新穎的受NRF2調控的基因, c-Fos和EID3。使用西方墨漬法、染色質免疫沉澱法及發光脢法,我們發現NRF2會辨認且結合在c-Fos和EID3的啟動子上的抗氧化反應元件(ARE)以促進其表現。此外,我們建構了在角質細胞特定表達活化的NRF2的轉殖小鼠模型。我們也測試了是否NRF2過度活化能改善頭頸癌患者藉由輻射治療所出現的常見副作用口腔粘膜炎。 Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is now the second leading cause of cancer death worldwide. According to recently exome sequencing studies, many mutated genes and pathways implicated in HCC were identified. The most frequently mutated genes include TERT (59%), beta-catenin (10~32%), TP53 (18~35%), MLL (17~20%), JAK1 (9%), KEAP1 (8%) and NRF2 (6%). Mutation and aberrant accumulation of NRF2 in HCC may play important roles in promoting malignant progression during liver carcinogenesis. NRF2 executes cellular defenses against oxidative and electrophilic stresses and protects against chemical carcinogenesis. However, recent studies found that NRF2 is accumulated and activated in many types of cancer. In this study, we examine how NRF2 contributes to liver carcinogenesis. We found that knockdown of NRF2 by shRNA suppressed in vitro and in vivo cell proliferation, sphere formation, cell migration and cell invasion. Through microarray analysis, we identified novel NRF2-regulated genes, c-Fos and EID3. Using western blotting, chromatin immunoprecipitation, and promoter luciferase reporter assay, we found that NRF2 recognized an antioxidant response element (ARE) in the promoter of c-Fos and EID3 to upregulate their expression. In addition, we generated a mouse model of K14.NRF2 E82G, which express a constitutively active NRF2 transgene under the control of a keratin 14 promoter. We tested whether NRF2 overactivity improves oral mucositis, a common side effect of irradiation for patients with head and neck cancer. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/54499 |
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顯示於系所單位: | 病理學科所 |
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