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研究生:劉沁瑜
研究生(外文):Chin-yu Liu
論文名稱:LMX-1A基因對抑制子宮頸癌侵襲和轉移之相關性研究和轉移之相關性研究LMX-1A基因對抑制子宮頸癌侵襲和轉移之相關性研究
論文名稱(外文):Characterization of LMX-1A as a metastasis suppressor in cervical cancer
指導教授:賴鴻政賴鴻政引用關係
指導教授(外文):Hung-Cheng Lai
口試委員:黃世明朱堂元林雅雯陳永恩賴鴻政
口試委員(外文):Shih-Ming HuangTang-Yuan ChuYa-Wen LinMichanl W.Y. ChanHung-Cheng Lai
口試日期:2009-10-30
學位類別:博士
校院名稱:國防醫學院
系所名稱:醫學科學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:98
語文別:中文
論文頁數:66
中文關鍵詞:子宮頸癌附基因體學甲基化癌轉移
外文關鍵詞:LMX-1Acervical cancerepigeneticsmethylationmetastasis
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在癌症發生的過程中,DNA 甲基化扮演十分重要的角色,在癌症診斷上也具有生物標記及癌症篩檢的功能。在本實驗室先前的研究當中,我們使用附基因體學的研究策略,利用CpG島微陣列的方法(CpG island microarray),找尋子宮頸癌中可能被甲基化的基因,LMX-1A是其中之一。LMX-1A屬於LIM同源序列基因家族(LIM- Homeobox gene),從文獻研究中可知,目前已知的主要功能在於調控演化與生物發育,對癌症生成一無所悉。在本篇研究中,分別在子宮頸癌的細胞株、動物模式及人類檢體中分析LMX-1A這個轉錄因子的功能。在癌細胞中,LMX-1A因甲基化而被關閉,將其重新表現之後發現,LMX-1A並不影響癌細胞的生長與凋零,但顯著地影響癌細胞的聚落形成和侵襲能力。分析可能被調控的因子包括:CDH1、CDH2、VIMMENTIN、SNAIL、SLUG和TWIST等上皮間質標記(epithelial-mesenchymal-transition; EMT),部分參與了由LMX-1A所影響的抑癌作用。在shRNA的技術中,反向證實這些轉錄因子的確影響LMX1A癌細胞的癌化行為。在免疫缺損的小鼠的異種移植實驗中(xenograft study),發現LMX-1A具有抑制腫瘤生成和遠端轉移的功能;此外,我們分析了調控轉化生長素和骨頭成型蛋白訊息調控因子(TGF-/BMP signaling),也發現LMX-1A抑制BMP4和BMP6的表現。本研究的結果顯示,LMX-1A藉由不完全的EMT作用(incomplete EMT),成功地抑制子宮頸癌的侵襲和轉移。
最後,利用免疫組織化學法探討人類的正常子宮頸組織和腫瘤組織,輕度子宮頸上皮內腫瘤(low-grade cervical intraepithelial neoplasia ; CIN)、重度子宮頸上皮內腫瘤(high-grade CIN)、局部侵襲(locally–invasive)和遠端侵襲的組織(distant metastatic cancers), 支持LMX-1A在癌侵襲和癌轉移的抑制角色。
DNA methylation is important in cancer development and is a promising biomarker for cancer detection. An epigenomic approach used in our previous work showed that LMX-1A is methylation-silenced in cervical cancer. LMX-1A, a LIM-homeobox gene, is known to participate in developmental events; however, there are at present no data on the role of LMX-1A in cancers. In this study, we characterized the function of this transcription factor by examining cell lines, animal models and human cervical neoplastic tissues, and found that overexpression of LMX-1A does not affect cell proliferation or the cell cycle of cervical cancer cell lines but significantly inhibits colony formation and invasion in vitro. Analysis of changes in epithelial-to-mesenchymal transition (EMT) markers such as CDH1, CDH2, VIMENTIN, SNAIL, SLUG, and TWIST revealed involvement of the EMT in LMX-1A-mediated cancer invasion; this result was validated in a stable transfectant overexpressing LMX-1A with RNA interference. Furthermore, we found by analyzing TGF-/BMP signaling that BMP4 and BMP6 are down-regulated by LMX-1A. The results of this study suggest that LMX-1A suppresses cancer invasion and metastasis in cervical cancer through an incomplete EMT.
Xenograft studies using immunocompromised mice confirmed the suppressor effects of LMX-1A on tumor formation and distant metastasis in cervical cancer cell lines. LMX-1A immunohistochemical staining of tissue arrays containing the full spectrum of cervical neoplasms, including normal cervix, low-grade cervical intraepithelial neoplasia (CIN), high-grade CIN, locally–invasive and distant metastatic cancers, demonstrated the critical role of LMX-1A in invasion and metastasis.
正文目錄
第一章 緒論 1
第一節 子宮頸癌的危險因子 2
第二節 基因變化與子宮頸癌的相關性 3
第三節 附基因學與子宮頸癌的相關性 4
第四節 子宮頸癌中新穎甲基化基因的發現 5
第五節 LMX-1A基因及其家族 6

第二章 實驗材料與方法 8
第一節 LMX-1A在子宮頸癌細胞中基因表達分析 8
壹 、細胞培養 8
貳 、細胞全核醣核酸 (total RNA) 的萃取 9
參 、互補去氧核糖核酸(cDNA)的製備 9
肆 、反轉錄聚合酵素連鎖反應 (Reverse transcription polymerase chain reaction, RT-PCR) 10
伍 、定量聚合酵素連鎖反應 (Quantitative Polymerase Chain Reaction) 11
陸 、去甲基化藥物 5-AZA-2’-Deoxycytidine (5-Aza-CdR) 處理 12
第二節 LMX-1A表現載體的構築和來源 13
壹 、轉型作用 (Transformation) 及轉殖株落之確定 13
貳 、大量質體製備及純化 14
參 、轉殖作用 (Transfection) 15
肆 、RNA干擾下調LMX-1A的表現(short hairpin RNA; shRNA) 15
伍 、蛋白質的萃取 16
陸 、蛋白質濃度測定 16
柒 、蛋白質膠體電泳 (SDS-PAGE) 分析 17
捌 、西方墨點法(Western blot) 17

第三節 細胞癌化程度分析(Tumorigenicity assays) 19
壹 、細胞生長曲線分析(Growth curve analysis) 19
貳 、流式細胞儀分析細胞週期之變化(Flow cytometry) 19
參 、細胞株群落形成之分析 20
肆 、細胞株侵襲能力之分析(Invasion assay) 21
伍 、小鼠異位腫瘤移植模式實驗 21
陸 、小鼠異位腫瘤轉移模式實驗 22
柒 、組織微陣列(tissue microarrays)與免疫細胞組織染色 22
捌 、統計分析 23

第三章 結果 24
第一節 外源性LMX-1A抑制子宮頸癌細胞表現型的影響 24
壹 、內源性LMX-1A在子宮頸癌細胞中之表現 24
貳 、甲基化藥物5’aza-2’-deoxycytidine(5-Aza-CdR)對LMX -1A表現之影響 24
參 、外源性LMX-1A抑制癌細胞癌化表現 24
肆 、shRNA下調LMX-1A對子宮頸細胞癌化的影響 25
第二節 LMX-1A抑制癌細胞侵襲的可能機制探討 26
壹 、上皮間質轉換的調控 26
貳 、骨形成蛋白之訊息傳遞(Bone morphogenetic protien signaling; BMP) 26
第三節 LMX-1A對小鼠體內腫瘤細胞形成與轉移的影響 27
第四節 LMX-1A在臨床組織中的表現 28

第四章 討論 29
第一節上皮-間質轉換過程(Epithelial-Mesenchymal transition; EMT)在子宮頸癌侵襲和癌轉移中的過程扮演的角色 29
第二節LMX-1A和骨形成蛋白之訊息傳遞(Bone morphogenetic protein signaling; BMP)家族的關係 32
第三節 BMP和EMT之間的交互作用 34
第四節 LMX-1A與抑癌轉移因子(Metastasis Suppressor) 35

第五章 結論與展望 37
第六章 參考文獻 38
附錄 --- 發表之相關文章 66








表目錄
表1、同源序列基因和人類疾病之相關性 62
表2、各引子對和核酸序列 63
表3、BMP與癌症發生之文獻回顧 64
表四、抑癌轉移因子的相關訊息傳遞路徑 65


















圖目錄

圖1、婦女感染人類乳突病毒後發展為子宮頸癌的過程 43
圖2、人類乳突病毒參與子宮頸癌癌化過程的各階段 44
圖3、上皮細胞轉換為間質細胞的步驟 45
圖4、EMT轉換過程之細胞型態改變和其可能參與的分子機制 46
圖5、細胞內LMX-1A基因表現和5-aza-2’-deoxycytidine對基因表現的影響 47
圖6、於子宮頸癌細胞株內建立穩定表現LMX-1A的細胞株
圖6、(A)PCR檢測mRNA 48
圖6、(B)定量PCR檢測mRNA 49
圖6、(C)蛋白質檢測(西方墨點法) 50
圖7、外源性LMX-1A基因對子宮頸癌細胞生長速率的影響 51
圖8、外源性LMX-1A基因對子宮頸癌細胞週期的影響 52
圖9、外源性LMX-1A基因對子宮頸癌細胞內調控細胞週期相關基因的影響 53
圖10、(A)(B)LMX-1A基因對子宮頸癌細胞群落生長分析 54
圖10、(C)(D)LMX-1A基因對子宮頸癌細胞侵襲能力分析 55
圖11、LMX-1A基因對子宮頸癌細胞內EMT相關標記分析 55
圖12、LMX-1A基因對子宮頸癌細胞內BMP的影響 56
圖13、LMX-1A基因對小鼠腫瘤生成的影響 58
圖14、LMX-1A基因對小鼠體內癌轉移的影響 60
圖15、人類子宮頸癌組織內LMX-1A的表現 61
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