- 學位論文
探討TRIP13對食道鱗狀上皮細胞癌的影響
Investigate the role of TRIP13 in esophageal squamous cell carcinoma progression
摘要
食道鱗狀上皮細胞癌(ESCC)為全球最常見癌症之一。由於ESCC的高惡性度與化療抗藥性，導致ESCC患者的五年存活率遠低於30%。先前我們的DNA微陣列分析指出thyroid hormone receptor 13(TRIP13)在癌症組織中具有高mRNA的表現，且TRIP13已被證實與其他的癌症發展有關。但在食道癌，TRIP13的作用機轉與影響目前尚未明瞭。所以探討TRIP13是否會影響ESCC的發展與其作用機制為本研究的主要目的。在臨床的檢體中發現，35對ESCC患者的TRIP13 mRNA及蛋白質表現量，在癌症組織中有較高的表現。而TRIP13表現高的患者利用Kaplan-Meier存活率分析，發現其存活率有較低的趨勢。為了解TRIP13與ESCC之間的作用，利用兩株ESCC細胞株，CE81T與CE48T，建構出抑制與過度表現TRIP13的細胞，發現抑制TRIP13的組別其增殖與轉移的能力都有顯著的下降，反之過度表現TRIP13的組別則呈現促進的現象。另一方面，在過度表現TRIP13的組別中，利用順鉑(cisplatin)化療藥物所誘導的細胞凋亡數量，在流式細胞儀分析結果呈現顯著的下降的情況。同時過度表現TRIP13的組別，其下游產物Cyclin B1也有上升的趨勢。根據上述的結果，我們推測TRIP13可能在ESCC的發展中扮演重要的角色，而且能夠透過調控Cyclin B1促進ESCC的惡化。這項研究在未來可能為ESCC患者提供一個新的基因治療方針，提高患者的存活率。
並列摘要
Esophageal squamous cell carcinoma (ESCC) is one of the common cancers worldwide. ESCC has been recorded with highly metastatic rate and resistance to chemo-therapeutic drug. The aggressive characteristic of ESCC leads the patient’s 5-year overall survival rate lower than 30%. In our previous tissue microarray studies, we found a special gene called Thyroid hormone receptor interactor protein 13 (TRIP13). TRIP13, a member of AAA+ ATPase and is associated with several cancers progression. However, the relationship between TRIP13 and ESCC progression is still unclear. In this study, we investigated the influence of TRIP13 in ESCC cells progression, and chemo-resistance. In our clinical studies, 35 ESCC patient’s tumor tissues specimen from Kaohsiung Veterans General Hospital, specimens showed significantly high TRIP13 expression in both mRNA and protein levels. Kaplan-Meier analysis estimated that high expression of TRIP13 patents maybe correlated with low survival rate. Investigating the connection between TRIP13 and ESCC, TRIP13 was establish with knockdown and overexpression in two ESCC cell lines, CE81T and, CE48T. Overexpression of TRIP13 induced cancer cell proliferation and metastasis, inhibition of TRIP13 had the opposite result. Furthermore, flow cytometry analysis showed overexpression of TRIP13 decreased ESCC apoptotic cell numbers after chemo-therapeutic drug treatment. Also up-regulated TRIP13 in ESCC cells increase cyclin B1 protein expression except cyclin D. According to the result, TRIP13 may play an important role in esophageal squamous cell carcinoma development through regulated cyclin B1. This study maybe will provide a new target for genetic therapy and increase the survival rate of ESCC patients.