人類肺癌抑癌基因的研究

Abstract

肺癌的成因為肺組織中細胞不受控制的生長所致，而肺癌在所有癌症中是死亡率很高的癌症。根據 2008 年 WHO 的統計數字得知，當年度全球有高達 138萬人死於肺癌。而在這些肺癌病人中存活率達五年的人數只占了其中的 15%，足見其死亡率之高。肺癌又可分為兩個類別，其中非小細胞癌 (Non-small cell lung carcinoma, NSCLC) 為最常見的種類，非小細胞癌的病人大約有 30% 可在早期被診斷出癌症並進行手術的切除。然而，有高達 40% 的病人在五年內有復發的情形發生。研究肺癌病人的基因參與在肺癌的致病機轉是近幾年來研究肺癌的重要課題。從我們實驗室先前的研究中我們發現到 LCTS1 (Lung Cancer Tumor Suppressor 1) 基因在肺癌細胞中可能扮演著抑癌基因的角色。在本論文的研究中我們發現當 LCTS1 表現後，癌細胞發生生長變慢甚至死亡的現象。而透過一些實驗我們也發現，當 LCTS1 表現之後對於肺癌細胞的移動 (migration)、侵犯 (invasion) 以及增殖 (proliferation) 都有產生抑制的情形。造成肺癌的成因有許多都是因為某些基因像是 K-RAS、HER2或者是EGFR (Epidermal growth factor receptor) 產生不正常的活化或突變而導致的。於是我們進一步分析是否 LCTS1 對於 EGFR 有調控的現象。我們首先從網站上比對到 EGFR 的 promoter 含有兩個 EGFR 的結合位，並從西方點墨法 (western blotting) 的結果我們發現 LCTS1 的表現會影響癌細胞 EGFR 的活化。而當過量表現 LCTS1 的癌細胞打入老鼠後，我們也發現腫瘤的大小明顯的比對照組小很多。由上述結果，我們推論 LCTS1 在肺癌細胞中扮演了抑癌基因的角色。

Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung and accounts for 17% of the total deaths from cancer. According to the database of WHO, lung cancer is the most common cause of cancer-related death worldwide, and was responsible for 1.38 million deaths annually in 2008. The overall 5-year survival rate of the patients with lung cancer is less than 15%. Non-small-cell lung carcinoma (NSCLC) is the major type of lung cancer. Around 30% of NSCLC patients are diagnosed at an early stage of the lung cancer and receive curative surgery; however, the disease will relapse within 5 years in about 40% of the patients. It is urgently important to identify and understand the specific genes and their molecular mechanisms in these high-risk patients. In our previous studies, we identified LCTS1 (lung cancer tumor suppressor 1) as a candidate gene associated with disease progress of lung cancer. In the study, we used a lung cancer cells line, CL1-5, as a model to investigate whether LCTS1 is a potential tumor suppressor. Our results showed that LCTS1 decreased the proliferation rate of CL1-5 lung cancer cells and might also induce cell death. We also observed that overexpression of LCTS1 inhibited migration, invasion and proliferation ability of CL1-5 cells. It has been reported that some mutations in genes such as K-RAS, HER2 or EGFR were the factors responsible for lung cancer. We then supposed that whether LCTS1 could regulate the expression or activation of EGFR. By screening the DNA binding sites of LCTS1 on the website, we found that LCTS1 could bind to the promoter region of EGFR. The results of western blotting further indicated that LCTS1 repressed EGFR activation. From the in vivo xenograft model, we observed that the LCTS1-expressed tumor size was smaller than that of control. Taken together, these results indicated that LCTS1 might act as a tumor suppressor gene in lung cancer.