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研究生:劉怡君
研究生(外文):Yi-Chun Liu
論文名稱:評估CD98作為食道癌腫瘤幹細胞的表面抗原的可能性
論文名稱(外文):Evaluation of CD98 as The Potential Surface Marker of Esophageal Cancer Stem Cells
指導教授:陳燕彰陳燕彰引用關係
指導教授(外文):Yann-Jang Chen
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生命科學系暨基因體科學研究所
學門:生命科學學門
學類:生物訊息學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:英文
論文頁數:44
中文關鍵詞:食道癌腫瘤幹細胞CD98
外文關鍵詞:Esophageal cancerCancer stem cellsCD98
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腫瘤幹細胞是指在腫瘤細胞中一小群具有幹細胞特性的癌細胞。其具有自我更新的能力,並且對藥物及放射線有抵抗性。食道癌在東亞地區是很常見的癌症,但我們對食道癌腫瘤幹細胞的表面抗原所知卻有限。因此,我們實驗室設計了一個較精確的篩選平台以分離出較純的食道癌腫瘤幹細胞。接者利用基因表現微陣列晶片進行表面抗原的篩選,同時藉由文獻分析,我們將研究目標放在CD98這個蛋白上。CD98是由一重鏈(CD98hc)和一輕鏈(CD98lc)所組成的細胞表面異二聚體。過去的研究已知道CD98的表現與腫瘤的發生和進展有所關聯。但其在食道癌腫瘤幹細胞中扮演什麼角色,卻是不清楚的。
為了瞭解CD98在食道癌腫瘤幹細胞中所扮演的角色,我們使用兩種食道癌細胞株,TE2以及CE-81T/VGH作為研究材料。首先,我們利用流式細胞分選儀,分離出不同CD98表現量的細胞,分成CD98Low、CD9825%、 CD9875%和 CD98High四組細胞。接著我們透過腫瘤聚球分析及幹細胞基因表現分析來比較這些分選細胞間的差異。並進一步透過抑制食道癌腫瘤幹細胞中CD98hc的表現來證明其對腫瘤幹細胞中幹細胞特性的重要性。
我們發現CD98High細胞具有較高表現的stemness及EMT相關的標記基因,分別是Oct4, Sox2, Klf4, c-Myc, Nanog, E-cad, Vim, Snail,且其聚球能力相較於其他組的分選細胞也較好。除此之外,抑制 CD98的表現會使食道癌腫瘤幹細胞的stemness及EMT相關的標記基因和蛋白的表現量降低,也會造成聚球形成的減少,此結果與有具有CD98高表現的情況相反。
本篇研究發現高表現量CD98可以調控食道癌腫瘤幹細胞的幹細胞能力以及細胞行為。另外,抑制CD98的功能會導致其在食道癌腫瘤幹細胞的幹細胞特性被抑制。我們認為CD98可以做為食道癌腫瘤幹細胞的標記,也可以利用此一生物標記,發展出新的食道癌治療的新策略。

Cancer stem cells (CSCs) are a small subset cell group that has stem cell characteristics in cancer. They are capable of self-renewal and are resistant to drugs and radiation treatment. Esophageal cancer is common in East Asia. However, there is limited information about the biomarker of esophageal CSCs. Our lab established a novel platform to isolate esophageal CSCs. After CSC isolation, we screened the expression of surface markers by expression microarray and literature searching, we then focused on CD98 as potential surface marker of esophageal CSCs. CD98 is a cell-surface heterodimer consisting of a ~80-85 kDa heavy chain (CD98hc) and a ~40 kDa light chain (CD98lc). CD98 expression is associated with the development and progression of many tumors.
To understand the role of CD98 in esophageal CSCs, two esophageal cancer cell lines, TE2 and CE-81T/VGH, were used. We first divided the cells into four group, CD98Low, CD9825%, CD9875%, and CD98High cells through FACS sorting. We then analyzed the characteristics of these sorting cells through tumor-sphere formation assay and stemness gene expression assay. Furthermore, we knockdowned CD98hc in esophageal CSCs to investigate its importance in CSCs stem-like properties.
Our results revealed that the CD98High cells expressed higher stemness and EMT markers in both mRNA and protein levels, including Oct4, Sox2, Klf4, c-Myc, Nanog, E-cad, Vim, and Snail. Their sphere formation abilities were considerably greater than other sorting cells (roughly two times of fold change). Moreover, the knockdown of CD98 reduced the expression of stemness and EMT markers and also decreased sphere-forming ability.
Taken together, high expression of CD98 might involve in regulating the stemness features and cell behavior of esophageal cancer stem cells. Suppression of CD98 might inhibit the stem-like properties of esophageal CSCs. CD98 might be the potential biomarker of esophageal cancers. Targeting the CD98 may provide a new strategy for esophageal cancer therapy.

中文摘要 i
Abstract iii
Contents v
Introduction 1
Esophageal cancer 1
A.Two subtypes of esophageal cancer 1
B.Signs and symptoms 2
C.Risk factors 3
Cancer Stem Cells (CSCs) 3
A.Features of CSCs 4
B.Limitation to the traditional therapy of cancer 4
C.Isolation of cancer stem cells 5
CD98 6
A.Biochemical functions 7
B.CD98 in cancer 8
C.CD98 in cancer stem cells 8
Specific Aims 10
Materials and Methods 11
Results 15
Identification of CD98 as surface marker for esophageal cancer stem cells 15
Knockdown of the SLC3A2 (encoded CD98hc) gene suppressing the expression of CSCs property 17
Discussion 19
References 22
Figures and Tables 30

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