| Abstract: | 肺癌是台灣女性和男性癌症死亡原因的第一和第二位。肺癌同樣是歐美先進國家的 首要癌症死因。已知 85% 以上之歐美國家之肺癌是抽菸者，但是台灣不到一半的 肺癌患者有抽菸習慣，尤其是女性僅有 4% 為抽菸者。因此環境因子在台灣肺癌 之形成，可能扮演重要之角色。鎳已被 IARC 公告為人類 group 1 之致癌物，主 要依據工人在鎳汙染染之工廠的長期職業暴露，增加罹患呼吸道癌症之風險。李輝 研究室過去以病歷對照組之研究結果顯示，鎳累積於肺癌患者之肺組織的含量顯著 高於非癌症者，並發現鎳之含量與患者之抽菸量無關，因此推測鎳汙染可能會增加 台灣中部地區罹患肺癌之風險。最近研究發現鎳汙染與台灣彰化地區之口腔癌發生 率較高有關。最近未發表之數據顯示土壤中鎳含量與台灣肺癌之發生率有正相關 性。李輝研究室最近之數據顯示，鎳在p53 突變之患者的肺組織中顯著高於 p53 正 常之肺癌患者，因此鎳可能會抑制DNA 修補能力而增加p53 發生突變之風險。已 知鎳不僅會抑制 DNA 修補能力造成參與肺腫化基因之突變，同時還會產生 ROS 引起氧化壓力以及經由 TLR4/NF-kB 造成慢性發炎反應。因此本計畫將由鎳引起 之慢性發炎反應探討IL-10, Nrf2 和GSTM2 等與免疫調節、抗氧化和解毒有關基因 之表現，在環境汙染物—鎳暴露所引起之不抽菸肺腫瘤化之角色。本計畫另以大鼠 動物模式探討肺臟分佈最廣之Vagus C-fibers 的鎳刺激是否會釋放出大量之ROS， 在引起肺臟慢性發炎和前趨腫瘤化之角色。鎳會活化NF-kB 路徑引起慢性發炎， IKK beta 是活化NF-kB 路徑之關鍵步驟，本計畫將由植物化學物 (phytochemicals) 中尋找IKK beta 具有強效之抑制劑，用來預防鎳暴露引起之慢性發炎以及肺腫瘤 化。因此本群體計畫包括五個子計畫分別由IL-10, Nrf2, GSTM2, 和Vagus C-fibers 探討鎳暴露引起之慢性發炎，在不抽菸肺癌之分子致腫瘤分子機轉。並將尋找抑制 IKK beta 之植物化學物，以預防鎳引起之慢性發炎之肺癌形成。總之，本計畫之結 果將有助於預防鎳引起之肺癌發生以及提出可能有效之臨床預後生物標記和治療 策略，以減少不抽菸肺癌之發生和延長患者之存活期和生命品質。
Lung cancer is leading cause of cancer death in worldwide including Taiwan. Cigarette smoking is the major factor for lung cancer incidence. However, more than 50% of Taiwanese lung cancer is nonsmokers, especially in women who are only 4% smokers. Therefore, environmental factors may play an important role in lung cancer development in nonsmokers. Nickel has been considered to be a group 1 human carcinogen by IARC. However, this was only supported by epidemiological studies from workers by occupation exposure, not general population exposed by environmental contamination. Our previous case-control study indicated that nickel content in lung tissues from lung cancer patients was significantly higher than those from non-cancer controls, suggesting that nickel may contribute to lung cancer development in Taiwan. Nickel contamination in soil was found to be associated with oral cancer incidence in Changhua County, Taiwan. Our recent data showed that p53-mutated lung cancer patients had higher nickel contents than p53-wildtype patients. These results raised us to expect that nickel environmental contamination could contribute to lung cancer development in Taiwan. It is well known that nickel may induce ROS production to cause NF-kB activation and chronic inflammation. Chronic inflammation has been considered to link with lung tumorigenesis, especially in adenocarcinomas. In this team project, we will investigate the role of IL-10, Nrf2, and GSTM2 which was an inflammatory, antioxidant and phase II detoxification gene in nickel-associated lung tumorgiensis. Vagus C-fibers are abundantly distributed in lung organs and vagus C-fibers excitation has been shown to result in ROS production. Therefore, we will investigate the role of vagus C-fibers stimulated by nickel may induce to lung inflammation and may contribute to lung tumorigenesis. IKKbeta activation is the key event for activation of NF-kB signaling pathway. Therefore, we expect that IKKbeta activation may play a crucial role in nickel-associated lung tumorigenesis. In this team project, we will search specific and efficient inhibitors from naturally-occurring phytochemicals to prevent nickel-induced inflammation and lung tumorigenesis. Therefore, we have 5 component projects in this team project to investigate the role of nickel contamination in Taiwanese nonsmoking lung tumorigenesis. These results obtained from this team project may be helpful to prevent nickel-associated lung cancer development. The results from underlying mechanism studies will establish feasible prognostic biomarkers to predict patient’s survival and relapse and provide possible therapeutic strategies to improve patient’s survival and life quality. |
