| Abstract: | 肺癌是台灣?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?到一半的肺癌患者有抽菸習慣，尤其是?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? 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??，增加?患呼吸道癌症之風險。?輝研究室過去以病?對照組之研究結果顯示，鎳?積於肺癌患者之肺組織的含?顯著高於非癌症者，並發現鎳之含?與患者之抽菸?無關，因此推測鎳汙染可能會增加台灣中部地區?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?較高有關。最近未發表之?據顯示土壤中鎳含?與台灣肺癌之發生?有正相關性。?輝研究室最近之?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?而增加p53 發生突變之風險。已知鎳?僅會抑制 DNA 修補能?造成?與肺腫化基因之突變，同時還會產生 ROS 引起氧化壓?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??所引起之?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?激是否會釋放出大?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 ?徑引起慢性發炎， IKK beta 是活化NF-kB ?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?預防鎳??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??引起之慢性發炎，在?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?床預後生物標記和治?策?，以減少?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. |
