- 學位論文
運動失調毛細血管擴張症突變相互作用因子在癌症進程中之角色
The role of ataxia telangiectasia mutated interactor in cancer progression
摘要
癌症是目前世界上非常棘手的問題，也是臨床上病人死亡的重要疾病之一。雖然它已被研究長達數十年，但是目前對它的致病機轉及治療方針瞭解並不完全。不同的癌症種類，例如：口腔癌及大腸直腸癌，甚至於不同亞型，像是大腸癌中的微星粒不穩定型(MSI)及穩定型(MSS)致病機轉及治療結果也不盡相同。在本研究中，我們透過微陣列分析出的幾個特殊基因，期望找出其在不同癌症中的調控機轉。運用高通量的分析方法偵測調控癌症轉移的可能下游影響分子，並使用即時聚合酶鏈鎖反應法分析病人檢體來確認這些基因的角色，包括：ataxia telangiectasia mutated interactor (ATMIN)，同時進一步分析其與臨床預後的關係。藉由體外細胞株給予或去除基因來評估其功能，及原位注射或脾臟注射的小鼠動物模式來觀察淋巴轉移及肝臟轉移，研究結果發現ATMIN的高表現量與口腔癌及大腸癌中微星粒穩定型的臨床期別成正比且病人預後較差，但卻與微星粒不穩定亞型的臨床期別成反比而病人預後較佳。總結來說，基因的功能仰賴不同的癌症或亞型而有不同的影響力，相信此論文提供了未來癌症個人化醫療之重要的參考證據。
並列摘要
Cancer is the serious issue worldwide and responsible for many deaths. Even though it has been studied for several decades, it is still mysterious. The different cancer types, such as oral squama cancer cell (OSCC) and colorectal cancer cell (CRC), and even the same cancer with different subtypes, such as CRC microsatellite instable (MSI) and CRC microsatellite stable (MSS), come out with different ways. In this study, we aimed to explore the roles of several genes that were identified by microarray analysis and their regulatory mechanisms in different cancer types. The high throughput analysis was used to detect the downstream effectors of target gene-regulated metastasis. The cancers specimens were detected by Quantitative RT-PCR to confirm the roles of the genes, including ataxia telangiectasia mutated interactor (ATMIN), and were analyzed with these gene expression and clinical outcomes by Kaplan–Meier analyses. The functions of ectopic genes expression or silencing on cell behavior were evaluated in vitro. Lymph node metastasis and liver metastasis abilities were investigated by orthotropic and splenic injection in animal model. Interestingly, ATMIN mRNA expression was correlated with advanced stages in OSCC and CRC/MSS, but negatively correlated with CRC/MSI population. Moreover, in vivo animal experiments were confirmed the result as clinical samples. In conclusion, the gene functions were various depending on cancer types even subtypes, it provides the strong evidence for personalize medical treatment.