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系統識別號 U0026-0608201517324600
論文名稱(中文) 探討 PGRMC1 在肝癌中的角色
論文名稱(英文) The study of progesterone receptor membrane component 1 in hepatocellular carcinoma
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 103
學期 2
出版年 104
研究生(中文) 林柔君
研究生(英文) Jou-Chun Lin
學號 T36021065
學位類別 碩士
語文別 中文
論文頁數 73頁
口試委員 指導教授-何中良
口試委員-黃溫雅
口試委員-楊孔嘉
口試委員-蔡弘文
中文關鍵字 肝癌  孕酮受體膜蛋白單元 1  細胞增生  抗藥性  5-fluorouracil  XTT assay 
英文關鍵字 HCC  PGRMC1  cell proliferation  drug resistance  5-fluorouracil  XTT assay 
學科別分類
中文摘要 肝癌為全球最致命的惡性腫瘤且治療方式有限的癌症之一,其主要的危險因子有 B 型肝炎、C 型肝炎、酒精性肝病和非酒精性脂肪肝病。近年出現許多以訊息傳遞分子為標的之標靶治療抑制劑,例如:以 EGFR 為標靶的 Gefitinib 及 Erlotinib 和以 MET 為標靶的 SU11274。就這一點而言,膜受體對於分子標靶治療來說是一好的標靶,且對於在未來分析每個肝癌病人其分子的表現譜,進而選擇合適的標靶治療也是越來越重要的。罹患肝癌的機率為男性高於女性,而此現象進一步被臨床的觀察所支持,即患有慢性肝病的男性會比女性較快速的發展成肝硬化,因此肝硬化導致肝癌的發生被認為主要是男性及停經的女性的疾病。然而,男性和女性的性荷爾蒙及其受體在肝癌中的確切作用仍知之甚少。
為了尋找與肝癌相關之新的生物標誌,我們利用肝癌和鄰近非腫瘤的肝組織進行 MALDI-IMS 及 SDS-PAGE 之實驗。且透過 in-gel digestion 與 MS/MS 之分析找出幾個有興趣的基因,其中包含屬於 MAPR family 的孕酮受體膜蛋白單元 1 (progesterone receptor membrane component 1, PGRMC1)。PGRMC1 為膜上黃體素受體 (membrane progesterone receptor) 其中的一員且最初由豬的肝臟分離出來。PGRMC1 是一較小蛋白質 (25 kDa),其整個 PGRMC1 分子為黃體素的結合與反應所需的。PGRMC1 被視為腫瘤細胞增生的生物標誌,且大量的表現於不同的癌症中,例如:卵巢癌、乳癌及肺癌。臨床上,我們發現 PGRMC1 的表現量若在肝癌組織中為下降的話,其與較差的無病生存期有關。在體外實驗中,我們將肝癌細胞株利用 knockdown 及 overexpression 的方式並進一步探討 PGRMC1 與 EMT、癌幹性、細胞增生、抗藥性 (將5-fluorouracil 加入細胞中) 及自噬作用之間的相關。藉由西方墨點法發現 PGRMC1 與 EMT 及癌幹性都無相關,然而,其與自噬作用似乎有相關性。最後,利用 XTT 分析後發現 PGRMC1 與肝癌細胞的增生及抗藥性有關,若過度表現 PGRMC1,則肝癌細胞的增生及抗藥性會下降;反之,若 knockdown PGRMC1,肝癌細胞的增生及抗藥性則會上升。
英文摘要 To identify novel biomarkers associated with HCC, we have performed both MALDI-imaging and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) on histology-proven HCC and adjacent non-tumor liver tissues. In-gel digestion with tandem mass spectrometry identified several interesting genes, including progesterone receptor membrane component 1 (PGRMC1) that belongs to membrane-associated progesterone receptor (MAPR) family. By using clinical specimen, we found that PGRMC1 is down-regulated in many HCC tissues which correlates with worse disease-free survival. In vitro, we used knockdown and overexpression approaches in the HCC cell lines to further evaluate the role of PGRMC1 in epithelial-mesenchymal transition (EMT), cancer stemness, cell proliferation, drug resistance, and autophagy. We found that PGRMC1 was neither associated with epithelial-mesenchymal transition (EMT) nor cancer stemness by western blot analysis. However, it seemed related with autophagy. Furthermore, PGRMC1 was related with cell proliferation and drug resistance through XTT assay. PGRMC1 overexpression decreased cell proliferation and reduced drug resistance in HCC cell lines. On the other hand, PGRMC1 knockdown increased cell proliferation and enhanced drug resistance in HCC cell lines.
論文目次 摘 要...................................................I
Abstract..............................................III
致 謝..................................................VI
目 錄.................................................VII
表 目 錄................................................X
圖 目 錄...............................................XI
第一章 緒論.............................................1
1.1 肝細胞癌概論.........................................1
1.2 肝細胞癌與膜受體訊息傳遞系統之關係......................5
1.3 肝細胞癌與性賀爾蒙及賀爾蒙受體間的關係..................6
1.3.1 肝細胞癌與雄性賀爾蒙及雄性賀爾蒙受體的關係.............6
1.3.2 肝細胞癌與雌性賀爾蒙及雌性賀爾蒙受體的關係.............9
1.4 孕酮受體膜蛋白單元 1 (progesterone receptor membrane component 1, PGRMC1) 之介紹............................12
1.5 癌症中的 PGRMC1 與化療藥物之間的關係..................14
1.5.1 PGRMC1 與表皮生長因子及對於 erlotinib 的敏感度之間的關係.....................................................14
1.5.2 PGRMC1 在子宮肉瘤中與 doxorubicin 之間的關係........16
1.6 PGRMC1 與自噬作用 (autophagy) 間的關係...............17
1.7 實驗目的............................................18
第二章 實驗材料與方法....................................20
2.1 細胞的培養程序......................................20
2.2 細胞相關實驗........................................22
2.3 分子生物技術........................................25
2.4 Cell proliferation assay – XTT (Roche)............38
2.5 統計分析............................................39
第三章 實驗結果.........................................40
3.1 分析 PGRMC1 在腫瘤/非腫瘤 (tumor/non-tumor) tissue paires中的表現量........................................40
3.2 分析患有 HCC 之病人體內 PGRMC1 表現量多寡與其復發率的關係.....................................................40
3.3 分析 PGRMC1 在九種 HCC 細胞株中的表現量...............41
3.4 產生穩定 knockdown 及過度表現 PGRMC1 之 HCC 細胞株....42
3.4.1 從 PGRMC1 基因編碼區域 (coding region) 篩選有效的RNAi 標的序列................................................42
3.4.2 構築表現 PGRMC1 全長之反轉錄病毒感染系統表現質體.....42
3.5 探討 PGRMC1 與上皮細胞中胚轉化 (EMT) 之相關性.....................................................43
3.6 觀察 PGRMC1 與 HCC 細胞株生長速率之差異性.....................................................44
3.7 探討 PGRMC1 與 HCC 細胞株對於 5-FU 抗藥性之關係.......44
3.8 探討 PGRMC1 與癌幹性 (cancer stemness) 之相關性.....................................................45
3.9 探討 PGRMC1 與自噬作用 (autophagy) 之相關性.....................................................45
第四章 討論.............................................47
第五章 參考文獻.........................................52
第六章 表...............................................62
第七章 圖...............................................63
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