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研究生:張幸治
研究生(外文):Chang, Shing-Jyh
論文名稱:探討早期與晚期第一型子宮內膜癌基因差異
論文名稱(外文):Exploration of genomic differences between early and advanced endometrial endometrioid carcinoma
指導教授:張大慈莊永仁
指導教授(外文):Chang, Dah-TsyrChuang, Yung-Jen
學位類別:博士
校院名稱:國立清華大學
系所名稱:分子與細胞生物研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:英文
論文頁數:76
中文關鍵詞:子宮內膜癌上皮前驅細胞生物晶片機器學習
外文關鍵詞:Endometrial endometrioid carcinomaEpithelial precursorsMicroarrayMachine learning
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目前科學家已經認定癌細胞帶有與正常幹細胞相似的特徵,且癌細胞中的幹細胞基因表達程度與病人的預後相關。科學家最近發現表現Lgr5或CD133的上皮幹細胞容易產生惡性轉化,然而,目前仍不清楚哪些基因大量表現在此類上皮幹細胞以致發生惡性腫瘤。子宮內膜癌為女性前十大癌症之一,依組織形態分為二型:第一型與第二型,第一型子宮內膜癌佔較多數。國際婦產科聯盟依據腫瘤侵襲與轉移程度將子宮內膜癌分為4期,癌症分期數較高的病人存活率較低。鑑定晚期癌細胞與幹細胞間共有的基因將可揭露出惡性腫瘤的發生機制,並提供新穎的治療研究標的。
由基因體層次將早期(第一與第二期)與晚期(第三與第四期)第一型子宮內膜癌的分子特徵分辨出來,即有機會在晚期第一型子宮內膜癌中找出上皮幹細胞基因,本研究發現ERBB2 (HER2/neu)與CCR1基因在晚期的第一型子宮內膜癌中被活化,而腫瘤抑制基因APBA2 (MINT2)與CDK抑制物p16卻在早期癌細胞中被活化。在晚期癌細胞中MAPK訊息傳遞鏈受到正向調控,意味可能治療晚期第一型子宮內膜癌的藥物標的存在於此傳遞鏈中。另外,從免疫組織染色實驗確認致癌基因ERBB2 (HER2/neu)大量表現在晚期癌組織中。進一步利用演算法將這些分子特徵精緻成6基因微特徵,即可分辨早期與晚期第一型子宮內膜癌。從分子特徵分析中明顯發現晚期侵襲性第一型子宮內膜癌具有上皮幹細胞的基因表現特性,說明這些腫瘤較惡性的原因。
本研究對於第一型子宮內膜癌的發病原理提供新的見解,並揭露成人幹細胞與第一型子宮內膜癌病理特徵之間的未知連結。晚期第一型子宮內膜癌具有上皮幹細胞基因,或許為造成晚期腫瘤具類幹細胞表現的原因,此類上皮幹細胞基因也許可作為藥物治療標的與新穎的預後生物標記。未來將更進一步評估標的在ERBB2的現有臨床藥物作為治療第一型子宮內膜癌的可能性,具體應用本論文之研發成果。

It has been recognized that cancer cells acquire characters reminiscent of those of normal stem cells, and the degree of stem cell gene expression correlates with patient prognosis. Lgr5(+) or CD133(+) epithelial stem cells (EpiSCs) have recently been identified and these cells are susceptible to neoplastic transformation. It is unclear, however, whether genes enriched in EpiSCs also contribute in tumor malignancy. Endometrial endometrioid carcinoma (EEC) is a dominant type of the endometrial cancers and is still among the most common female cancers. Clinically endometrial carcinoma is classified into four FIGO (International Federation of Gynecology and Obstetrics) stages by the degree of tumor invasion and metastasis, and the survival rate is low in patients with higher stages of tumors. Identifying genes shared between advanced tumors and stem cells will not only unmask the mechanisms of tumor malignancy but also provide novel therapeutic targets.
To identify EpiSC genes in late (stages III-IV) EECs, a molecular signature distinguishing early (stages I-II) and late EECs was first characterized to delineate late EECs at the genomics level. ERBB2 and CCR1 were genes activated in late EECs, while APBA2 (MINT2) and CDK inhibitor p16 tumor suppressors were in early EECs. MAPK pathway was significantly up regulated in late EECs, indicating that drugs targeting this canonical pathway might be useful for treating advanced EECs. Immunohistochemistry (IHC) staining on another independent tissue set confirmed the overexpression of ERBB2 (HER2/neu) oncogene in advanced EECs. A six-gene mini-signature was further identified to differentiate early from advanced EECs in both training and testing datasets. Advanced, invasive EECs possessed a clear EpiSC gene expression pattern, explaining partly why these tumors are more malignant.
This study provides new insights into the pathogenesis of EECs and reveals a previously unknown link between adult stem cells and the histopathological traits of EECs. Shared EpiSC genes in late EECs may contribute to the stem cell-like phenotypes shown by advanced tumors and hold the potential of being candidate therapeutic targets and novel prognosis biomarkers. The possibility of repurposing existing clinical drugs against ERBB2 for the treatment of EECs is awaited to be evaluated.

致謝 I
中文摘要 II
Abstract III
List of Contents IV
List of Tables VI
List of Figures VII
List of Abbreviations VIII
Chapter 1 Introduction 1
1. Endometrial Cancer 1
1.1. Anatomy 1
1.2. Epidemiology 1
1.3. Risk Factors 2
1.3.1. Hormones 2
1.3.2. Genetics 3
1.3.3. Previous Irradiation 3
1.3.4. Other Co-morbidities 4
1.3.5. Protective Factors 4
1.4. Pathogenesis 4
1.4.1. Pathology of Hyperplasia 5
1.4.2. Pathology of Endometrioid Adenocarcinoma 6
1.4.3. Molecular Pathology and Biology of Endometrioid Adenocarcinoma 7
1.5. Staging 8
1.6. Prognosis 8
1.6.1. Stage 9
1.6.2. Histologic Subtype 9
1.6.3. Depth of Invasion and Grade 9
1.6.4. Adnexal Involvement and Lymphovascular Invasion 10
1.6.5. Positive Peritoneal Cytology 10
1.6.6. Age 10
2. Hypothesis of Cancer Stem Cell 10
3. Aims, Experimental Design and Significance 13
Chapter 2 Materials and Methods 14
1. Microarray Data Sets 14
2. Array Data Processing 14
3. Bioinformatics Analysis 15
4. Immunohistochemical Staining 16
Chapter 3 Results 17
1. Molecular Signatures of Early and Late Stage EECs 17
2. In-depth Exploration of EEC-related Genes 18
3. A Six-gene Signature Distinguishing Early and Late EECs 20
4. Re-activation of Epithelial Stem Cell Genes in Advanced EECs 21
Chapter 4 Discussion and Prospects 23
References 30
Tables and Figures 42

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