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研究生:吳孟鄉
研究生(外文):Meng-hsiang Wu
論文名稱:多環芳香烴類受器及CytochromeP4501B1在人類正常與腫瘤肺組織之表現情形
論文名稱(外文):Aryl Hydrocarbon Receptor and Cytochrome P450 1B1 Expression in Human Normal Lung as well as Lung Tumor Tissues
指導教授:林嬪嬪林嬪嬪引用關係
指導教授(外文):P. Lin
學位類別:碩士
校院名稱:中山醫學院
系所名稱: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:2001
畢業學年度:89
語文別:中文
論文頁數:86
中文關鍵詞:多環芳香烴類受器腫瘤肺組織細胞色素P450IB1肺癌非小細胞肺癌Aryl hydrocarbon hydroxylase 酵素測定西方墨點法組織免疫染色法
外文關鍵詞:cytochrome p4501B1lung cancerAhRArntpolycyclic aromatic hydrocarbonB[a]PAryl hydrocarbon hydroxylase
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目前肺癌高居台灣地區男性及女性癌症死因第二及第一位。許多研
究顯示肺癌的發生與暴露環境中的致癌物有關,例如多環芳香烴類化合物(polycyclic aromatic hydrocarbons , PAH)。Benzo[a]pyrene(B[a]P)是一種廣泛分布於環境中的PAH,例如存在於香菸煙霧懸浮微粒、空氣懸浮微粒、廚房中烹調時所產生之油煙及二手菸。B[a]P進入人體後會與AhR(aryl hydrocarbon receptor)及Arnt(AhR nuclear translocator)鍵結,誘導cytochrome P450 1A1 (CYP1A1)、1A2、1B1等基因表現及酵素活性,這些酵素可代謝B[a]P成為具致癌性之代謝物,因此AhR表現程度可能影響細胞對B[a]P之反應。另外有研究指出CYP1B1在許多腫瘤組織中之表現程度高於週邊之正常組織。因此本研究之目的為(1)比較正常支氣管上皮細胞及肺癌細胞株之AhR及Arnt蛋白表現程度以及B[a]P在這些細胞株中抑制生長、誘導aryl hydrocarbon hydroxylase(AHH)酵素活性及CYP1B1蛋白表現之能力;(2)以組織免疫染色法檢測正常肺組織與肺腫瘤組織中,AhR及CYP1B1蛋白二者之表現情形及相關性,並且分析與其他臨床資料之關係。本研究中發現B[a]P對不同肺細胞株抑制細胞生長,及誘導AHH酵素活性之程度有明顯差異。5株肺癌細胞株中AhR蛋白表現程度分別與B[a]P抑制細胞生長及誘導AHH酵素活性有關(r2=0.7445及0.7225),雖然CYP1B1被誘導程度與AhR蛋白表現無關,但AhR表現量最高的H1355細胞,在本質上表現CYP1B1蛋白,因此細胞中AhR高度表現,可能促使CYP1B1本質上表現。接著利用組織免疫染色法發現AhR主要表現在正常支氣管上皮細胞及肺腫瘤細胞之細胞質中,而且52.6﹪(41/78)的肺腫瘤細胞之AhR蛋白表現量高於週邊鄰近之正常支氣管上皮細胞。比較肺癌病人其腫瘤組織與非腫瘤組織mRNA表現情形時,也發現66.7﹪(4/6)腫瘤組織中AhR mRNA表現量高於非腫瘤組織。另外AhR在肺腺癌腫瘤組織中表現量高於肺鱗狀細胞癌(p=0.004),我們在大腸癌及口腔癌組織也觀察到AhR過度表現的現象。先前細胞實驗證實肺細胞株之CYP1B1可被B[a]P誘導,因此進一步觀察正常肺組織與肺腫瘤組織中CYP1B1表現情形。相同地,CYP1B1也表現在正常支氣管上皮細胞及腫瘤細胞之細胞質,而在非抽煙者之肺腫瘤組織CYP1B1表現比抽煙者高(p=0.046),而且肺腺癌組織CYP1B1表現量高於肺鱗狀細胞癌(p=0.006)。由於腫瘤組織中AhR過度表現,而且AhR可能調控CYP1B1表現,因此進一步分析肺腫瘤組織中AhR與CYP1B1表現程度之相關性,發現AhR和CYP1B1表現量成正相關(p=0.001),但是在抽煙者中二者無統計上之相關性。總而言之,我們發現肺腫瘤組織中AhR與CYP1B1蛋白過度表現,尤其在非抽煙者及肺腺癌,而且二者表現程度具相關性。因此AhR所調控之CYP1B1表現在非抽煙者及肺腺癌病人的癌症發生過程中可能扮演某種角色。

Lung cancer is the first and second leading cause of cancer death among female and male in Taiwan, respectively. Several studies showed that the occurrence of lung cancer is associated with exposure to environmental carcinogens such as polycyclic aromatic hydrocarbons (PAH). PAH are present in air particles, smoke produced during cooking or cigarette smoking. PAH bind to aryl hydrocarbon receptor (AhR) in cells, and induce the gene expression and enzyme activities of cytochrome P450 1A1 (CYP1A1), 1A2 and 1B1. These induced enzymes convert PAH into carcinogenic metabolites. There are studies showing that CYP1B1 expression is higher in tumors than in normal tissues. Therefore, the objective of this study is to (1) study the correlations among growth inhibition by benzo[a]pyrene (a PAH), induction of aryl hydrocarbon hydroxylase (AHH) enzyme activity, and protein expression of CYP1B1 and AhR in normal bronchial epithelium and lung cancer cell lines; (2) compare the expression and correlation of AhR and CYP1B1 proteins in normal lung tissues and lung tumors using the immunohistostaining method.
We found that the levels of AhR protein correlated with growth inhibition by B[a]P in these cell lines. When we examined AhR expression and localization in normal lung tissues and lung tumors with the immunohistostaining method, we found that AhR predominantly expressed in cytoplasm. Furthermore, 60﹪(3/5) of normal bronchial epithelium expressed high levels of AhR. Fifty three percent (41/78) of lung tumors expressed higher levels of AhR proteins than adjacent normal bronchial epithelium. In addition, AhR showed higher expression in adenocarcinoma than squamous cell carcinoma (p=0.004). Sixty seven percent (4/6) of tumor tissues showed higher mRNA expression of AhR than non-tumor tissues in lung cancer patients.AhR was also overexpressed in 64﹪(9/14) colon cancer and 57﹪(4/7) oral cancer tissues.
Previously, we demonstrated that CYP1B1 was inducible by B[a]P in lung cancer cell lines. We found that CYP1B1 was also expressed in the cytoplasm of normal bronchial epithelium. Lung tumors of non-smokers have higher levels of CYP1B1 than of smokers (p=0.029), and adenocarcinoma have higher levels of CYP1B1 than squamous cell carcinoma (p=0.002). A positive correlation between AhR and CYP1B1 expression levels was found in tumors (p=0.001). However, there was no significant correlation for smokers. In summary, we found that AhR and CYP1B1 were overexpressed in lung tumors, especially in non-smokers and lung adenocarcinoma, and their expression was well-correlated. Therefore, our data suggest that AhR plays an important role in the expression of CYP1B1 in lung tumors.

壹、中文摘要1
貳、英文摘要4
參、縮寫6
肆、前言7
伍、材料與方法
一、材料27
1.材料與藥品27
2.人類肺癌細胞株之來源28
3.檢體來源28
二、方法
1.細胞培養、分盤 29
2.RNA純化30
3.半定量RT-PCR31
4.Aryl hydrocarbon hydroxylase (AHH)酵素活性測定33
5.蛋白定量分析34
6.西方墨點法35
7.免疫組織染色法37
8.免疫組織染色結果之判讀38
9.統計分析39
陸、結果
一、 比較B[a]P對人類正常支氣管上皮細胞株與肺癌細胞株 細胞生長之影響41
二、 比較B[a]P在人類正常支氣管上皮細胞株與肺癌細胞株 中誘導AHH酵素活性之能力44
三、 比較人類正常支氣管上皮細胞株與肺癌細胞株之AhR、 Arnt蛋白表現量47
四、 比較B[a]P在人類正常支氣管上皮細胞株與肺癌細胞株 中誘導CYP1B1蛋白表現之能力49
五、 比較人類正常肺組織與肺癌組織中AhR蛋白表現之情 形51
六、 利用半定量RT-PCR比較肺癌病人其非腫瘤組織與腫瘤 組織之AhR mRNA相對表現量58
七、 比較正常肺組織與肺腫瘤組織中CYP1B1蛋白的表現情 形60
八、比較同一肺癌病人其非腫瘤組織與腫瘤組織(配對之組織)中AhR、CYP1B1蛋白表現情形65
九、肺腫瘤組織中AhR與CYP1B1表現之相關性67
十、不同腫瘤組織中AhR表現之情形69
柒、討論72
捌、圖表目錄29
圖一、處理B[a]P對人類正常支氣管上皮細胞株與肺癌細胞株生長之影響43
圖二、正常支氣管上皮細胞株與肺癌細胞株中,B[a]P誘導AHH酵素活性之程度46
圖三、(A)BEAS-2B、H23、H1355、CH27、H226及Calu-1細胞株中,AhR與Arnt之蛋白表現程度(B)AhR及Arnt蛋白量化圖48
圖四、(A)BEAS-2B、H23、H1355、CH27、H226及Calu-1細胞株中,B[a]P誘導CYP1B1蛋白表現之程度(B) CYP1B1蛋白量化圖50
圖五、人類攝護腺肥大組織之上皮細胞中AhR免疫染色結果53
圖六、人類肺癌組織中AhR免疫染色結果56
圖七、病人組織AhR與GADPH之mRNA表現程度59
圖八、人類肺腫瘤組織中CYP1B1免疫染色結果62
圖九、大腸癌、乳癌、口腔癌之AhR免疫染色結果71
表一、人類正常肺組織之肺腫瘤組織之AhR表現情形54
表二、肺腺癌與肺鱗狀細胞癌中AhR表現情形55
表三、在肺腺癌與肺鱗狀細胞癌中AhR蛋白過量表現之情 形57
表四、同一病人其肺腫瘤組織與非肺腫瘤組織中AhR mRNA 表現情形59
表五、人類正常肺組織與肺腫瘤組織中CYP1B1蛋白表現情 形63
表六、肺腺癌與肺鱗狀細胞癌中CYP1B1表現情形64
表七、同一病人其非腫瘤肺組織與肺腫瘤組織(配對之組織) 中AhR與CYP1B1蛋白表現情形66
表八、肺腺癌與肺鱗狀細胞癌中AhR與CYP1B1蛋白表現 之相關性68
表九、在不同腫瘤組織與其鄰近非腫瘤組織中AhR表現之 情形70
玖、附錄、附圖
附錄一、AhR與Arnt之結構15
附錄二、AhR與Arnt之結構功能16
附錄三、AhR/Arnt調控CYP1A1基因表現之路徑圖19
附圖一、AhR表現量、AHH酵素活性、CYP1B1被誘導量 之相關性73
拾、參考文獻77

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