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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 郭彥彬 | |
| dc.contributor.author | Hao-Hueng Chang | en |
| dc.contributor.author | 章浩宏 | zh_TW |
| dc.date.accessioned | 2021-06-08T07:02:49Z | - |
| dc.date.copyright | 2009-02-17 | |
| dc.date.issued | 2009 | |
| dc.date.submitted | 2009-01-23 | |
| dc.identifier.citation | 英文文獻
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IARC Monographs programme finds betel-quid and areca-nut chewing carcinogenic to humans. http://www.iarc.fr/en/Media-Centre/IARC-Press-Releases/Archives-2003-1998/2003/IARC-Monographs-programme-finds-betel-quid-and-areca-nut-chewing-carcinogenic-to-humans. 行政院衛生署國民健康局網站 Bureau of Health Promotion, Department of Health, Taiwan, R.O.C http://www.bhp.doh.gov.tw 中華民國行政院衛生署衛生統計資料網 http://www.doh.gov.tw/statistic/index.htm | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/26204 | - |
| dc.description.abstract | 第二型組蛋白去乙醯酶(Histone deacetylase 2, HDAC2)被認為與某些人類腫瘤的發育與進展有關。 本研究先以免疫組織化學染色探討HDAC2於口腔鱗狀上皮細胞癌中的表現。研究結果顯示，HDAC2的陽性染色表現可在80/93 (86%)的口腔癌及11/20 (55%)的口腔上皮變異患者檢體中偵測到。主要出現於上皮細胞之細胞核中。 陽性標記指數(Labeling index, LI) 分別為25.8 ± 26.5% (口腔上皮變異)及 59.8 ± 28.5% (口腔鱗狀細胞癌)。正常口腔組織則無表現。在口腔鱗狀細胞癌的病例中，HDAC2的LI與性別、年齡、口腔習慣上並無顯著的關連。然而，在較後期的癌症分期、較大的腫瘤、或是淋巴轉移的病例中HDAC2皆有較高的表現。在Kaplan-Meier存活率分析方面， 較高的HDAC2表現(LI>50%)、較晚的癌症分期、較大的腫瘤或是具淋巴轉移之案例其存活率皆較低。
由於HDAC2過度表現在實體腫瘤中所扮演的角色至今仍不明瞭，因此我們擬繼續探討HDAC2在臺灣口腔癌癌化的角色。由於前述淋巴轉移的病例中，HDAC2皆有較高的表現， 因此我們首先嘗試探討 HDAC2 是否與癌細胞的移動與侵襲有關。 我們測試了實驗室中所擁有的多株口腔癌細胞株，發現都有HDAC2表現，其中 SAS, Ca9-22, Cal27表現較高， TW2.6, TW1.5, SCC9表現較低。恰與其侵襲能力呈正相關。利用實驗室中所分離出來的TW2.6口腔癌細胞株 及Transwell invasion chamber分離出較具轉移能力的次細胞株，將之命名為CC1-2, -4, -6。發現HDAC2基因表現的強弱與侵襲能力有正相關。因此HDAC2可能經由增強細胞之入侵能力而造成口腔癌侵襲性增強的表現。 本研究進一步以人類口腔癌細胞株SAS及Ca9-22來探討已被證實有很好的口服耐受性的HDACI- suberoyl anilide bishydroxamine (SAHA)對口腔癌細胞的影響。 結果顯示，以0.5-5 μM SAHA處理SAS及Ca9-22 細胞，可以明顯抑制其生長，且濃度愈高或作用時間愈長，抑制效應就愈明顯 (IC50分別為1.5μM & 3μM)。 在西方墨點法分析中，SAHA會增加SAS及Ca9-22細胞 PARP cleavage的情形，亦證實SAHA可引起人類口腔癌細胞的細胞凋亡。因此HDACI可做為未來治療口腔癌的潛力新藥物。 本實驗結果首次顯示出HDAC蛋白的過度表現在口腔癌案例中為一常見之現象，並可能作為一種口腔鱗狀細胞癌之預測因子及未來開發治療用藥之參考。 | zh_TW |
| dc.description.abstract | Histone deacetylase 2 (HDAC2) has been implicated in the development and progression of several human tumors. We immunohistochemically examined the expression of HDAC2 protein in 20 cases of oral epithelial dysplasia (OED) and 93 cases of oral squamous cell carcinoma (OSCC). Positive HDAC2 nuclear staining was observed in 80 of the 93 (86%) cases of SCC and 11 of the 20 (55%) cases of ED. The labeling index (LI) for HDAC2 nuclear staining increased significantly from ED (25.8 ± 26.5%) to SCCs (59.8 ± 28.5%) (p < 0.001). No significant correlation was found between the HDAC2 expression level and patient's age, sex, and oral habits in oral SCC patients. However, cancer with advanced stage, larger tumor size, or positive lymph node metastasis had higher level of HDAC2 protein expression. Kaplan-Meier curves showed oral SCC patients with high HDAC2 expression (LI >50 %), advanced stage, larger tumor size, or positive lymph node metastasis had significantly shorter overall survival (p=0.0158, 0.0267, 0.0029 and 0.02514, respectively by log-rank test) than others. The results of this study show for the first time that overexpression of the HDAC protein is a frequent event in oral cancer and could be used as a prognostic factor in oral SCC. We further investigated the role(s) of HDAC2 in oral carcinogenesis. We found that human oral cancer TW2.6 CC-2, -4, -6 cells with higher invasive ability exihibited higher HDAC2 expression.Recent studies have demonstrated that HDAC inhibitors (HDACIs) possess antitumor activity and are well tolerated, supporting the idea that their use might be a specific strategy for treatment of oral cancer. In this study, we investigate the effect of suberoyl anilide bishydroxamine (SAHA, one of the most potent HDACI) on SAS and Ca9-22. Here, we demonstrated that SAHA induces apoptosis in SAS and Ca9-22 cells as evidenced by PARP cleavage and nuclear DNA fragmentation ELISA. In combination with the clinical findings, the present stady demonstrated that HDAC2 may also play a role in regulating the invasive ability of oral cancer cells. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T07:02:49Z (GMT). No. of bitstreams: 1 ntu-98-D90422004-1.pdf: 6962088 bytes, checksum: 8948a0285701938c6a53a8a7bcf13bd6 (MD5) Previous issue date: 2009 | en |
| dc.description.tableofcontents | 表目錄 IV
圖目錄 V 中文摘要 6 英文摘要 8 誌 謝 10 第一章 緒論 11 第二章 文獻回顧 14 2.1 第一節 口腔鱗狀細胞癌之概觀 (Oral Squamous Cell Carcinoma, OSCC) 14 2.1.1 全球口腔癌之流行病學 14 2.1.2 口腔鳞狀細胞癌在台灣之情況 14 2.1.3 口腔鳞狀細胞癌之發生可能病因與致病機轉 15 2.1.4 口腔鳞狀細胞癌臨床病理分類及治療發展 19 2.2 第二節 HDAC 家族導論( Overview of the HDAC Family) 21 2.2.1 基因與癌症發生之關連 21 2.2.2 基因(geneifics)與基因外顯性(epi-genetic)調控與癌症之關連 22 2.2.3 組蛋白與組蛋白乙醯基轉移酶與組蛋白去乙醯化酶 23 2.2.4 HAT及HDAC種類介紹 24 2.2.5 HDAC和癌症之關係 25 2.2.6 組蛋白去乙醯化酶抑制劑(Histone deacetylase inhibitors) 27 2.2.7 細胞凋亡及其分子機轉 30 2.2.8 HDAC抑制劑誘導腫瘤細胞凋亡 31 第三章 材料與方法 33 3.1 標本之收集及臨床資料庫之建立 33 3.2 標本之固定及包埋 33 3.3 免疫組織化學染色 33 3.4 口腔癌細胞株之培養 36 3.5 西方墨點方法 37 3.6 入侵能力測試 40 3.7 MTT assay 41 3.8 Cell Death Retection ELISA 41 3.9 統計方法 41 第四章 結果 43 4.1 第一節 HDAC2 在口腔正常上皮(normal oral epithelial, NOE)口腔上皮變異(oral epithelial dysplasia ,OED)及口腔鱗狀上皮癌(OSCC)的表現 43 4.2 第二節 免疫化學組織染色結果與臨床病理因子的關係 43 4.3 第三節HDAC2在口腔鱗狀上皮細胞癌細胞株的表現(HDAC2 expression in the oral SCC cell lines) 44 4.4 第四節HDAC2 對於腫瘤入侵能力之影響 48 第五章 討論 51 第六章 結論 57 第七章 表與圖 58 第八章 附圖 79 參考文獻 81 發表文章(Publications) 88 圖目錄 圖一 HDAC2於正常上皮組織及腫瘤細胞之表現 58 圖二 Kaplan-Meier plots分析93例OSCC的存活曲線 59 圖三 HDAC在不同口腔癌細胞株之表現 60 圖四 口腔癌細胞株作入侵能力檢測 61 圖五 口腔癌細胞株作入侵能力檢測之量化圖 62 圖六 以經Transwell Invasion Chamher分離出較具移動能力之細胞株 63 圖七 利用Transwell Invasion Chamber分離出較具侵襲能力的次細胞 64 圖八 HDAC在口腔癌細胞株TW2.6及次細胞株TW2.6 CC-2,-4,-6之表現 65 圖九 使用MTT assay測定SAHA對細胞生長的影響 66 圖十 利用Cell Death Detection ELISAPLUS kit測量細胞的apotosis值 67 圖十一 以西方墨點法來證明，SAHA對調控細胞凋亡的相關蛋白質之影響 68 圖十二 SAHA 和 VPA處理口腔癌 SAS 細胞 69 表目錄 表1 實驗標本之HDAC2 核染色之評分分佈 70 表2 HDAC2蛋白表現與病人年齡、性別及腫瘤發生部位之相關性 71 表3 HDAC2蛋白表現與病人TNM中TN之相關性 72 表4 HDAC2蛋白表現與病人TNM分期階段之相關 73 表5 HDAC2蛋白表現與病人年齡、性別及腫瘤發生部位之相關性 74 表6 以年齡及多變項相對分析用以評估HDAC2蛋白表現與存活相關之腫瘤因子之相關性分析 75 表7 HDAC2蛋白表現與病人咀嚼檳榔習慣之相關性 76 表8 HDAC2蛋白表現與病人飲酒習慣之相關性 77 表9 HDAC2蛋白表現與病人吸菸習慣之相關性 78 | |
| dc.language.iso | zh-TW | |
| dc.subject | 口腔鱗狀細胞癌 | zh_TW |
| dc.subject | 組蛋白去乙醯酶 | zh_TW |
| dc.subject | Oral squmous cell cancer | en |
| dc.subject | histone deacetylases (HDAC) | en |
| dc.title | 第二型組蛋白去乙醯酶在口腔鱗狀上皮細胞癌之表現 | zh_TW |
| dc.title | Expression of histone deacetylase 2 (HDAC 2) in oral cancer patients | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 97-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 江俊斌,郭生興,張國威,張龍昌 | |
| dc.subject.keyword | 組蛋白去乙醯酶,口腔鱗狀細胞癌, | zh_TW |
| dc.subject.keyword | histone deacetylases (HDAC),Oral squmous cell cancer, | en |
| dc.relation.page | 106 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2009-01-23 | |
| dc.contributor.author-college | 牙醫專業學院 | zh_TW |
| dc.contributor.author-dept | 臨床牙醫學研究所 | zh_TW |
| 顯示於系所單位： | 臨床牙醫學研究所 | |
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