台灣地區大腸直腸癌及肺腺癌與多環芳香烴受器之相關性研究

The relationship between colorectal and lung adenocarcinoma and aryl hydrocarbon receptor in Taiwan

張 菡(Han Chang)

指導教授 ： 林嬪嬪 ； 周明智

中山醫學大學/醫學院/醫學研究所/博士(2006年)

https://doi.org/10.6834/CSMU.2006.00028

摘要

臺灣地區從民國71年始，癌症即高居民眾死亡原因的第一位。衛生署民國93年報告指出肺癌及大腸直腸癌分居民國88年癌症死因的第一位及第三位。暴露環境化學毒物是肺癌及大腸直腸癌的致病因子之一。環境化學毒物包括香煙煙霧 (BaP是代表物) 與戴奧辛 (TCDD是代表物)。流行病學的資料顯示，暴露這些物質會增加民眾罹患肺癌及大腸直腸癌的危險性。BaP與TCDD是多環芳香烴受器 (AhR) 之配基。標的細胞暴露BaP與TCDD後，能活化AhR，進而促進調控細胞色素P450 1酵素 (CYP1)基因表現，代謝產生致癌性中間產物，可能使細胞進行惡性轉化。動物實驗證實BaP與TCDD具有致癌性，且經由AhR訊息傳遞路徑。因此，致癌性AhR配基之暴露可能藉由活化它們的受器與增加特定CYPs表現而參與癌化過程。近年來，研究顯示CYP1B1在人類大腸直腸癌及肺腺癌細胞株及組織有過度表現 (overexpression) 的現象。人類肺腺癌之AhR過度表現與CYP1B1表現呈正相關。因此，AhR的活化及CYP1酵素的過度表現可能參與人類惡性腫瘤之形成。既然AhR配基及CYP1酵素與人類惡性腫瘤之形成相關，本研究的目的有三：1) 檢定肝臟及肺臟細胞對AhR配基的選擇敏感性；2)以大腸直腸癌與肺腺癌”腺瘤-腺癌”模式，檢定AhR及CYP1B1表現的情形；3)檢定抽煙、AhR或CYP1B1表現與肺腺癌預後之相關性。實驗結果顯示TCDD誘導公小鼠所產生之肝毒性，其病理變化，包括：肝細胞水腫 (edema)、肝血竇擴張 (sinusoidal dilatation)、脂肪變性 (fatty change)、及局部肝壞死 (focal hepatic necrosis)。TCDD誘導之肝毒性具有區域選擇性的敏感 (zonal selective sensitivity)，以中央小葉區之肝細胞對TCDD最敏感。在大鼠肺組織與人類肺細胞株中，TCDD/BaP誘導CYP1A1/CYP1B1表現主要於CCSP-positive cells (Clara cells)，因此bronchiolar Clara cell對於TCDD/BaP較basal cells或纖毛柱狀細胞敏感。在大腸直腸癌與肺腺癌”腺瘤-腺癌”模式研究中，資料顯示CYP1B1過度表現發生在癌前病變與侵犯性癌。因為CYP1B1過度表現開始於癌前病變(腺瘤)，所以推測CYP1B1參與大腸直腸癌與肺癌之早期癌化。已知香煙萃取物處理肺細胞株可以活化AhR，並且抽煙是肺癌的致病因子，本研究亦發現肺癌抽煙者平均存活時間比肺癌不抽煙者短 (Log rank test, p < 0.05)，因此抽煙可以作為預測肺癌預後的獨立指標。從肺腺癌存活與AhR或CYP1B1過度表現分析，AhR或CYP1B1蛋白質表現與肺腺癌預後無關。綜合言之，在肺腺癌與大腸直腸癌組織中，CYP1B1在腺瘤與腺癌過度表現，但是在正常黏膜上皮表現不強。這個重要的發現顯示CYP1B1過度表現可能参與人類肺腺癌與大腸直腸癌的早期癌化。此外更可以利用這個特性作為肺癌與大腸直腸癌早期診斷的指標。

關鍵字

多環芳香烴受器 ； 大腸直腸癌 ； 肺癌 ； 細胞色素P4501B1

並列摘要

Malignant neoplasms have been the leading cause of deaths in Taiwan since 1982. In 1999, lung cancer and colorectal cancer were the fist and the third leading cause of cancer deaths, respectively. Exposure to environmental carcinogens might be one of etiologies for human colorectal and lung cancers. For example, exposure to tobacco smoke (benzo[a]benzene, BaP, as a representative) and dioxins (2,3,7,8-tetrachlorodibenzo-p-dioxin ,TCDD, as a representative) increased the risk for colorectal and lung cancers. BaP and TCDD are ligands of aryl hydrocarbon receptor (AhR). Liganded AhR up- regulates expression of cytochrome P450 1 (CYP1) enzymes such as CYP1A1 and CYP1B1 in target cells. Several animal studies demonstrated that carcinogenicity of BaP and TCDD was AhR-dependent. Furthermore, CYP1B1 overexpression was found in colorectal and lung adenocarcinomas but limited in normal mucosa. AhR overexpression was positively correlated to CYP1B1 expression in lung adenocarcinomas. Thus, AhR signaling pathway might be involved in the development of the colorectal and lung adenocarcinomas. Since exposure to AhR ligands and CYP1 expression were associated with the development of lung and colorectal cancers, the objectives of this study were: 1) to identify specific cell populations those are sensitive to AhR ligands in liver and lung; 2) to examine AhR and CYP1B1 expression in an“adenoma-carcinoma” sequence of colorectal and lung adenocarcinomas; 3) to determine the relationship between AhR/CYP1B1 expression and survival or prognosis of lung adenocarcinoma. Our results showed that TCDD-induced liver pathology included edematous hepatocytes, sinusoidal dilatation, fatty change and hepatic necrosis in male ICR mice. TCDD-induced liver toxicity revealed a zonal selective sensitivity, with centrilobular hepatocytes being more sensitive to TCDD than bile duct cells or endothelium. In rat lung slices and human lung cells, TCDD/BaP induced CYP1A1/CYP1B1 expression mainly in CCSP-positive cells (Clara cells). These results suggested that bronchiolar Clara cells were more responsive to TCDD or BaP than basal cells and columnar cells. In“adenoma-carcinoma”models of human colorectal and lung adenocarcinomas, CYP1B1 overexpression occurred in adenoma/preinvasive lesions and carcinomas of colorectum and lung. This finding implied that CYP1B1 overexpression might play a role at the early stage of carcinogenesis in colorectal and lung adenocarcinomas. Tobacco smoke concentrate can activate AhR and cigarette smoking is the major cause for lung cancers. In this study, the mean survival time was 4 months less in cigarette smokers than non-smokers with lung cancers (Log rank test, p < 0.05). Thus cigarette smoking might be an independent poor prognostic factor for lung cancer. As well, neither AhR nor CYP1B1 overexpression was associated with cancer survival of lung adenocarcinomas. In summary, CYP1B1 overexpression was observed in adenoma/preinvasive lesions and adenocarcinomas of colorectum and lung but limited in normal epithelial cells. This important finding implied that CYP1B1 overexpression involved in the early development of colorectal and lung adenocarcinomas. Moreover, this differential expression of CYP1B1 between neoplasms and normal epithelia might be used as a biomarker for early diagnosis of colorectum and lung cancers.

並列關鍵字

aryl hydrocarbon receptor ； colon cancer ； lung cancer ； cytochrome P4501B1

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