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研究生:何宗殷
研究生(外文):Tsung-Ying
論文名稱:台灣肺癌患者之 Nrf2 和 Keap1 基因突變之研究
論文名稱(外文):Gene mutations of Nrf2 and Keap1 in lung tumorsfrom Taiwanese lung cancer patients
指導教授:李輝李輝引用關係
學位類別:碩士
校院名稱:中山醫學大學
系所名稱:醫學分子毒理學研究所
學門:醫藥衛生學門
學類:其他醫藥衛生學類
論文種類:學術論文
論文出版年:2010
畢業學年度:98
語文別:中文
論文頁數:72
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肺癌高居我國近十年來死亡率前一、二名。 (行政院衛生署國民健康局。2010) 。 Nrf2-Keap1 訊息傳遞路徑所調控的抗氧化與 Phase II 解毒基因對於腫瘤形成可能扮演很重要的角色。Keap1 在氧化壓力下會使 Nrf2 進入細胞核,結合至抗氧化基因的 antioxidant response element (ARE) ,啟動抗氧化基因的轉錄活性,以移除氧化壓力。有研究顯示肺癌患者之 Nrf2 和 Keap1 基因會發生突變,這些突變促進了 Nrf2 往核內的轉移並活化 Antioxidant response element (ARE) 所調控之下游基因的表現。這些研究也顯示 Nrf2-Keap1 路徑的活化可能參與腫瘤的發展且使得患者有較差的臨床預後。已知肺腺癌之形成機制與慢性發炎有關,而慢性發炎大多經由 ROS 所引起,但是台灣肺癌之 Keap1-Nrf2 路徑之活化機制是否是經由 Keap1 和 Nrf2 之基因突變所致,至今仍不清楚。因此本研究擬以 DNA 定序法來瞭解肺癌患者之肺腫瘤組織中,Nrf2 和 Keap1 基因是否會發生突變? 以及兩者突變率是否較過去之研究結果為高? 本研究完成 67 位肺癌患者之 Keap1 基因突變之分析,結果僅有兩位患者發生突變,(Codon 191, GCC to CCC, Ala to Pro) 和 (Codon 210, GCC to CCC/T, Ala to Pro),其突變率為 3.0%,遠低於日本與美國之肺癌患者之 Keap1 突變率 (3.3%~18.5%)。本研究另外完成 149 位肺癌患者之 Nrf2 基因之突變分析,結果發現僅有 4 位患者發生突變,(Codon 235, ATG→GTG, Met→Val),(Codon 588, GAT→AAT, Asp→Asn) ,(Codon 624, AAA→GAA, Lys→Glu) 和 (Codon 575, CCT→CTT, Pro→Leu),其發生突變之頻率為 2.7%,同樣較日本,韓國以及美國之 Nrf2 基因突變頻率為低 (6.9%~10%)。因此本研究之結果顯示,台灣肺癌患者主要不是經由 Keap1 和 Nrf2 基因發生突變活化 Keap1-Nrf2 路徑參與肺腫瘤化,可能有其他分子機制活化 Keap1-Nrf2 之路徑。

Lung cancer is the most common cause of cancer-related death worldwide. Similarly, it is the leading cause of cancer-related death in Taiwan. Antioxidant and Phase II detoxification genes regulated by Nrf2-Keap1 signaling pathway may play an important role in lung tumorigenesis. Nrf2 nuclear translocation has been shown to be controlled by Keap1. Keap1-Nrf2 heterodimer was dissociated under oxidative stress and then Nrf2 translocated into nucleus and bound with antioxidant response element (ARE) to upregulate antioxidant genes to remove ROS. Mutations of Keap1 and Nrf2 genes have been found in lung tumors and both gene mutations increased Nrf2 nuclear translocation to upregulate ARE-response gene expressions. These studies also showed that activation of Nrf2-Keap1 signaling pathway may promote tumor progression, and patients get poor prognosis. Lung adenocarcinoma tumorigenesis is considered to be associated with chronic inflammation and ROS is involved in lung inflammation. Therefore, aberrant Nrf2-ARE pathway could increase ROS production to cause lung adenocarcinoma development. In this study, DNA sequence was performed to evaluate Nrf2 & Keap1 protein expressions in lung tumors. The data would be provided to verify whether the protein expression could be act as an independent prognostic factor to predict patients’ survival? We evaluated Keap1 mutation in 67 lung cancer patients. Keap1 gene mutations were detected in 2 patients, (Codon 191, GCC to CCC, Ala to Pro) and (Codon 210, GCC to CCC/T, Ala to Pro), (3.4%). The Keap1 gene mutation rate is lower than the Keap1 gene mutation rate in the patients of Japan and USA (3.3%~18.5). Others, we evaluated Nrf2 gene mutation in 149 lung cancer patients. Nrf2 gene mutations were detected in 4 patients, (Codon 235, ATG→GTG, Met→Val),(Codon 588, GAT→AAT, Asp→Asn) ,(Codon 624, AAA→GAA, Lys→Glu) and (Codon 575, CCT→CTT, Pro→Leu) , (2.7%). The Nrf2 gene mutation rate is lower than the Nrf2 gene mutation rate in the patients of Japan, Korea and USA (6.9%~10%).
Our results indicated that the lung cancer patients with lower Keap1 and Nrf2 mutation rate in Taiwan. These findings could be suggested that Keap1 and Nrf2 mutation in Taiwan lung tumors can not be the major pathway to activate tumorigenesis. We conclude that there are other molecular mechanisms to activate Keap1-Nrf2 pathway to promote the tumorigenesis of lung cancer


壹、 中文摘要 3
貳、 英文摘要 5
參、 文獻綜論 7
一、 肺癌流行病學 7
1. 肺癌流行病學的特徵 7
2. 肺癌的分類、臨床症狀以及預後 9
二、 Nrf2-ARE 路徑中各蛋白與癌症之相關性 12
1. Keap1 12
2. Nrf2 13
2.1 Nrf2的功能 13
2.2 Nrf2訊息傳導方面的調控 15
2.3 Nrf2 穩定性方面的調控 19
3. Nrf2-Keap1 路徑與p53之相關性 21
肆、 研究動機 23
伍、 材料與方法 24
一、 材料與藥品 24
二、 檢體來源與收集 25
三、 實驗方法 26
1. DNA萃取 26
2. PCR 26
3. PCR產物純化與基因定序分析 28
4. 免疫組織化學染色法(Immunohistochemistry; IHC) 30
5. 統計分析 31
陸、 結果與討論 32
一、 Keap1 基因之突變以及與患者臨床因子的相關性 32
二、 Nrf2 基因之突變以及與患者臨床因子的相關性 34
三、 Nrf2 蛋白表現與肺癌臨床因子的相關性 36
四、 Keap1 蛋白表現與肺癌臨床因子的相關性 38
柒、 參考文獻 39
捌、 表與圖 57
玖、 參考與附圖 65


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行政院衛生署國民健康局 (2010)
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郭壽雄 (1998) 肺癌當代醫學


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