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研究生:陳藝文
研究生(外文):Yi-Wen Chen
論文名稱:Gelsolin扮演在口腔癌化過程與上皮細胞分化之角色
論文名稱(外文):The Role of Gelsolin in Oral Keratinocyte Differentiation and Carcinogenesis
指導教授:謝達斌
指導教授(外文):Ta-Pin Hsieh
學位類別:碩士
校院名稱:國立成功大學
系所名稱:分子醫學研究所
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:2003
畢業學年度:91
語文別:英文
論文頁數:116
中文關鍵詞:上皮細胞口腔癌
外文關鍵詞:Oral KeratinocyteCarcinogenesisGelsolin
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根據衛生署2002年統計資料顯示,口腔癌在台灣佔男性十大癌症之第五位,且在所有惡性腫瘤的盛行率有逐年攀升的趨勢,是目前擴展速度最快的癌症之一。流行病學研究發現在台灣檳榔嚼食的流行與此惡疾有明顯的關係。快速的周邊組織侵犯及遠隔轉移是口腔癌臨床治療失敗之主因,細胞運動可能在其中扮演重要角色。細胞運動主要是藉由肌動蛋白的動態調節達成。癌化過程中,已知肌動蛋白調控蛋白包括gelsolin等表現量均有明顯改變。過去研究已知在許多人類癌症中,gelsolin表現下降,且在一些癌組織之大規模基因體掃描實驗中也証明它是表現量最顯著受到抑制的蛋白質之一。然而,口腔癌發展與gelsolin之間的關係尚未被研究過。本研究主要目的在探討gelsolin與口腔癌癌化、發展以及口腔上皮分化之關係。免疫組織化學染色分析中發現,與正常組織比較,癌前組織與癌組織其gelsolin表現減少。然而,當癌細胞由癌前發展為癌或是發生轉移,gelsolin表現均有統計上的增加。此外,侵犯性生長模式、較大的腫瘤以及較年輕的口腔癌患者,gelsolin表現量均較高。病人的預後方面,gelsolin表現量的增加與較佳的預後相關。研究中另外發現gelsolin與腫瘤分化程度有關,其程度可表現在involucrin染色程度上。組織中involucrin高表現的癌細胞也表現較高的gelsolin。此發現在口腔癌細胞株的西方轉漬法分析中亦得到印證,並且involucrin表現量與gelsolin有顯著劑量上的正相關性。而相對於正常口腔上皮黏膜細胞,癌前與癌細胞株gelsolin表現量亦下降,與臨床之組織染色觀察結果吻合。在細胞分化之因果關係分析方面,提高培養液鈣離子濃度與飽和培養造成之口腔癌細胞株分化誘導,gelsolin表現會隨著分化程度而上升。利用ecdysone表現系統調節gelsolin表現可誘導口腔癌細胞分化,顯示其調控口腔癌細胞的分化之功能。此外,超表現gelsolin於OEC-M1口腔癌細胞株導致細胞生長減緩,進一步研究則發現是經由去氧核糖核酸合成速度下降,而非細胞衰亡增加所致。然而,當細胞以去除血清之刺激誘導凋亡進行,超表現gelsolin的細胞株其細胞凋亡的數目明顯增加。為進一步了解gelsolin的功能性角色與臨床上觀察到的組織進犯之關聯性,實驗中利用基因調控之口腔癌細胞模型以Transwell chamber assay以及曠時攝影來評估。Gelsolin確能促進細胞侵犯Matrigel的能力,然而對於細胞移動則呈現些微抑制或是無關聯。顯示在機動蛋白調控外gelsolin於促進細胞進犯上另有一特殊尚未被發現之途徑。在gelsolin之epigenetic表現調節方面,實驗中以組織蛋白去乙醯化之抑制劑觀察組織蛋白乙醯化對gelsolin基因表現的作用,發現gelsolin表現明顯上升並且能執行其下游之功能性影響。然而去甲基化劑則無影響。顯示口腔癌中gelsolin表現可能是經由組織蛋白乙醯化而非去氧核糖核酸甲基化所調控。
綜觀之,gelsolin表現在口腔癌臨床上具有預後之指標意義尤其於初期癌症並且與如癌細胞進犯行為等臨床病理因子有關。以細胞株模型及基因調控作功能性探討的後續研究中進一步發現gelsolin在促進癌進犯力之結果卻非經由增強細胞運動能力達到。Gelsolin超表現使癌細胞去氧核糖核酸合成受到抑制但並未增加凋亡細胞之比例。然而gelsolin的高表現則則使癌細胞對特定細胞凋亡路徑之誘導更為敏感。研究中更發現gelsolin在口腔癌細胞之分化扮演著功能性角色。顯然此一蛋白質在口腔癌化過程中扮演著多重的重要調節功能。
Oral squamous cell carcinoma (OSCC) is now ranked the fourth-leading cancer deaths in Taiwanese male population, owing to the prevalent betel quid chewing habits. Regional invasion to vital organs and distant metastasis were the most common cause of the clinical failure, in which cell motility may play a critical role. Gelsolin was known to regulate cell morphology maintenance, motility, cellular differentiation, and apoptosis. It was one of the most common down regulated protein in many types of human malignancies. However, the role of gelsolin in oral carcinogenesis has not been evaluated. In this study, we demonstrated that gelsolin expression was decreased in oral precancer and cancer lesions compared with normal oral mucosa. Nevertheless, a significant positive association between gelsolin expression and the cancer progression was observed. Clinicopathological evaluation revealed that gelsolin expression was correlated with the size of the tumor, the invasive growth pattern, and earlier onset of the disease. Significant higher five-year survival rate was associated with increasing gelsolin expression in the tumor cells especially among the early stage disease, implying the potential role of gelsolin as an independent prognostic biomarker in oral cancer. Interestingly, gelsolin expression in the tissues presented strong association with that of involucrin, an epithelial differentiation marker. The immunoblotting analysis in 13 lines including human OSCC, precancer lines and the primary cultured oral keratinocytes presented consistent results with the immunohistochemical data. In addition, Pierson analysis also revealed a dosage correlation between gelsolin and involucrin expression. The molecular mechanism of gelsolin expression in oral cancer cell motility and invasion, as well as cellular differentiation and apoptosis were further investigated in OSCC cell lines. Induction of differentiation by calcium concentration modulation and confluence culture both enhanced gelsolin expression. The ecdysone expression system was used to increase the gelsolin level in OEC-M1 cells. Upregulation of gelsolin also induced oral cancer cells undergoing differentiation suggesting a regulatory role rather than a consequence of the process. Overexpressing gelsolin in OEC-M1 cells suppressed cell growth rate via inhibiting DNA replication rate rather than enhancing apoptosis. However, gelsolin promoted cell apoptosis in response to serum deprivation. In addition, gelsolin expression did not or only slightly decrease cell motility, but significantly enhance cellular invasion into Matrigel. Treatment of OSCC cells with trichostatin A, a histone deacetylase (HDAC) inhibitor, enhanced gelsolin expression and promoted cancer cell death. However, there was no effect on 5-azacytidine (a demethylation agent) treatment. The data suggested that an epigenetic regulatory mechanism of histone acetylation could be one mechanism for gelsolin expression modulation in oral cancer cells. In summary, gelsolin expression is a significant biomarker of oral cancer progression. It may participate in oral carcinogenesis through the modulation of multiple functions in cell differentiation and apoptosis as well as cellular motility and invasion.
Abstract
English Abstract ....................................................i
Chinese Abstract. .............................................................iii
Acknowledge ...........................................................vi
Contents ..............................................................vii
Figure Contents .......................................................ix
Table Contents ........................................................x
Appendix Contents .....................................................xi
Introduction ..........................................................1
Oral cancer .........................................................1
Gelsolin ............................................................5
Materials and Methods ................................................. 17
Reagents and cell lines ...............................................17
Culture of normal oral keratinocytes and oral dysplasia and cancer cell lines 17
The induction and analysis of differentiation ........................18
Transfection and generation of stable cell lines .....................19
The ecdysone mammalian inducible expression system .....................20
Epigenetic regulation of gelsolin expression .........................21
Western blot analysis ................................................21
Patient population characteristics and specimen processing ...........23
Immunohistochemistry (IHC) ...........................................24
Interpretation of the staining result ................................25
The Invasion assay and the migration assay ...........................25
Time-lapse Videomicroscopy ........................................................27
WST-1 proliferation assay ............................................27
BrdU (5-bromo-2’-deoxyuridine) incorporation assay ..................28
Cell growth assay ....................................................28
FACS analysis ........................................................29
Statistic analysis .....................................................29
Results ................................................................31
Discussion .............................................................42
Summary ................................................................57
References ............................................................. 61
Figures ................................................................69
Tables .................................................................95
Appendix ...............................................................98
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