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研究生:藍婉民
研究生(外文):Wan-Min Lan
論文名稱:第一型血紅素氧化酶對於癌細胞增生及癌化進程之影響
論文名稱(外文):Effects of Heme Oxygenase-1 on Cancer Cell Growth and Progression
指導教授:趙麗洋林滿玉
指導教授(外文):Lee-Young ChauMaan-Yuh A. Lin
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:藥理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2010
畢業學年度:98
語文別:英文
論文頁數:56
中文關鍵詞:第一型血紅素氧化&第一型血紅素氧化&第一型血紅素氧化&第一型血紅素氧化&
外文關鍵詞:Heme oxygenase-1cancer progression
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第一型血基質氧化酶 (Heme oxygenase-1, HO-1) 為細胞內具有重要保護功能的酵素。當細胞受到如自由基、細胞激素等外界刺激時,HO-1會被誘發表現進而催化血基質的分解釋放出亞鐵離子、一氧化碳和膽綠素。一氧化碳和膽綠素具有許多細胞保護功能,如抗氧化、抗發炎以及抑制細胞凋亡等作用,因此HO-1被視為細胞內重要的氧化壓力感應及調節酵素。正常生理情況下,HO-1是藉由碳鏈末端上的一段穿膜結構鑲嵌於內質網膜上的蛋白質,而位於氮鏈末端的酵素活性區域則暴露在細胞質中。過去的研究顯示HO-1在許多癌化組織中大量表現。另外在臨床攝護腺癌組織切片中有觀察到HO-1在細胞核內表現的現象,且此進核現象與癌症惡性程度具高度相關性,這項結果指出HO-1的進核表現有參與癌化過程的可能性。藉由抗生素篩選建立大量表現全長HO-1 (f-HO-1,存在於內質網膜上)以及碳端穿膜區域剔除之HO-1 (t-HO-1,同時存在於細胞核與細胞質中)的穩定癌細胞株,以觀察HO-1對於癌細胞的形態、生長速度以及癌化進程中所需具備的能力如細胞爬行、侵襲之能力有何影響。實驗結果顯示f-HO-1大量表現之HeLa子宮頸癌穩定細胞株的細胞型態明顯地由原本排列整齊的上皮細胞形狀趨變成不規則紡錘狀的間質細胞型態,且細胞生長速度、細胞爬行以及侵襲的能力有明顯增進,此結果支持HO-1有促進腫瘤細胞增生以及增進癌細胞侵襲能力的現象;而此現象亦能在t-HO-1的穩定細胞株中明顯地觀察到。利用clonogenic survival assay將各穩定細胞株以非常低的細胞密度培養並照射不同強度之伽瑪射線後,發現f-HO-1細胞能抵抗高強度的放射線傷害並有較強的生存能力;然而t-HO-1卻對細胞無明顯地保護作用。為釐清HO-1是否透過其酵素活性而達成促進癌細胞生長等作用,利用HO-1抑制劑tin protoporphyrin以及建立失去酵素活性之突變型HO-1 (H25A點突變)穩定細胞株進行相同實驗,結果顯示受到活性抑制劑處理或完全缺乏酵素活性的f-HO-1促進癌細胞爬行或侵襲的能力皆明顯降低;然而t-HO-1卻不受顯著影響,仍能大幅增進癌細胞爬行與侵襲的能力。綜合以上實驗結果,可推論f-HO-1主要藉由其酵素活性促進癌細胞生長、癌化;而t-HO-1則是透過與酵素活性無關的途徑達成相同的促進癌細胞生長及癌化能力的作用。此外,為更進一步釐清此作用是來自於細胞質或細胞核內,將t-HO-1序列前端接上一段出核序列(nuclear export signal, NES),使t-HO-1只存在於細胞質當中。藉由細胞質體轉染後,進行細胞爬行及侵襲能力之比較,結果顯示存在於細胞質內的NES-t-HO-1無法增進細胞爬行及侵襲的能力,因此推論t-HO-1增進細胞癌化的能力主要是透過細胞核內之作用。
Heme oxygenase-1 (HO-1) is an important cytoprotective enzyme catalyzing the oxidative degradation of heme to liberate iron, carbon monoxide, and biliverdin. Carbon monoxide, biliverdin and its subsequent metabolite bilirubin possess cytoprotective functions including anti-oxidant, anti-inflammation and anti-apoptosis actions. Therefore, HO-1 is recognized as a critical oxidative stress sensor and regulatory system. HO-1 anchors in the endoplasmic reticulum (ER) through a single transmembrane segment located at the carboxyl-terminus. Previous studies revealed that HO-1 is induced in several cancers. Moreover, HO-1 is detected in nuclei of prostate cancer cells in clinical specimens and its nuclear localization is correlated with disease progression. These findings suggest that nuclear HO-1 may have a functional role in tumorigenesis or tumor progression. In this study, stable cell clones overexpressing full-length HO-1 (f-HO-1) with ER-anchorage and carboxyl-terminal truncated HO-1 (t-HO-1) with nuclear distribution were established and used to study the effects of different HO-1 localization on cancer cell morphology, proliferation, migration and invasion. We showed that HeLa cells overexpressing f-HO-1 exhibited epithelial to mesenchymal-like morphological change and enhanced proliferation rate, migration and invasion abilities. These phenomena were also observed in t-HO-1 overexpressing cells. Clonogenic survival assay demonstrated that overexpression of f-HO-1 but not t-HO-1 exerted significant cytoprotective effect against radiation hazard. Further experiments demonstrated that tin protoporphyrin, a HO-1 inhibitor, inhibited the migration and invasion abilities of cells overexpressing f-HO-1 but not the cells overexpressing t-HO-1. To further confirm this phenomenon, stable cell lines overexpressing activity-defective HO-1 mutants carrying alanine mutation at histidine 25 residue (H25A) were established. Results showed that H25A mutation abolished the enhanced migration and invasion abilities in cells overexpressing f-HO-1, whereas it had no effect on t-HO-1-mediated increase in cell migration and invasion. These results indicate that ER-anchored HO-1 causes more aggressive phenotype mainly through its catalytic activity; while t-HO-1 promotes cancer cell progression through an activity-independent mechanism. Moreover, to further clarify the phenomena were attributed to the effects of t-HO-1 in cytoplasm or inside nucleus, t-HO-1 with a nuclear export signal (NES) placed at its N-terminus was constructed and transfected to cells. Results showed that cytoplasmic localized NES-t-HO-1 failed to enhance the cell migration and invasion. These results indicate that t-HO-1 may promote cell migration/invasion mainly through its effects inside the nucleus.
Chinese Abstract ------------------------------------------ i
English Abstract ------------------------------------------ iii
Introduction ------------------------------------------ 5
1. Types of heme oxygenase (HO)
2. Functions of HO
3. Nuclear translocation of HO-1
4. Role of HO-1 in cancer

Specific aim ------------------------------------------ 11
Materials and Methods ------------------------------------------ 12
1. Chemicals and reagents
2. Antibodies
3. Plasmids construction
4. Cell lines
5. Western blot
6. Proliferation assay
7. Clonogenic survival assay
8. Migration assay
9. Invasion assay
10. Immunofluorescent staining
11. Statistics

Results ------------------------------------------- 22
Figures ------------------------------------------ 26
Discussion ------------------------------------------ 37
Conclusion ------------------------------------------ 43
References ------------------------------------------ 44

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