臺灣博碩士論文加值系統

第一部份
鼻咽癌是一種上皮細胞癌，極易發生頸部淋巴結轉移和遠端轉移。因而本研究主要探討趨化素受體 (chemokine receptors) 在鼻咽癌轉移過程中是否扮演重要的角色，此外也分析趨化素受體表現與放射線治療之間的關係。我們利用5株鼻咽癌細胞株 (TW01、TW04、HONE-1、BM-1和AS-1) 與取自48位鼻咽癌病人的52個腫瘤組織切片進行實驗。首先利用RT-PCR偵測5株鼻咽癌細胞株中，所有已知之趨化素受體 (CCR1-10、CXCR1-6和CX3CR1) 的mRNA表現，我們發現只有CCR7、CCR9、CXCR4和CXCR6表現量是比較有意義。接著用定量real-time RT-PCR確定五株鼻咽癌細胞株中CCR7、CCR9、CXCR4和CXCR6表現量，而流式細胞儀、趨化性分析與肌動蛋白聚合檢测也確認了表現在細胞膜上CCR7、CXCR4和CXCR6是有功能性；而CCR9則只表現在細胞質內不具功能。此外利用免疫組織化學染色針對52個鼻咽癌腫瘤細胞組織切片進行抗體免疫染色，我們發現幾乎所有原發癌的鼻咽檢體 (n= 12) 與病人已有近端轉移的鼻咽檢體 (n=15)，其CCR7、CXCR4和CXCR6表現皆呈陰性。然而二位已有肝臟轉移的病人之鼻咽檢體分別表現二或三種趨化素受體。此外近端或遠端轉移的腫瘤檢體，其CCR7、CXCR4和CXCR6的染色呈強陽性。統計後發現原發癌腫瘤和轉移癌腫瘤CCR7、CXCR4和CXCR6的表現量大不相同 （p < 0.001，p < 0.001 和 p < 0.002）。而我們也利用雷射擷取顯微切割 (laser capture microdissection, LCM) 技術，準確獲取5個新鮮冷凍原發癌腫瘤，及8個轉移癌的腫瘤細胞進行mRNA分析，結果與免疫化學染色有一致性結果 (CCR7、CXCR4 與 CXCR6分別為p = 0.05、0.03 和 0.03)。此外未治療組與放射線治療後組的CXCR4的表現也有很大差異 （1/22 比 5/8; p < 0.003)。因此我們認為CCR7、CXCR4和CXCR6在人類鼻咽癌轉移過程中會被表現，並且具有活性，其中CXCR4的表現還與是否曾經接受放射線治療有密切關係。
除此之外，我們還探討了4株鼻咽癌細胞株 (TW01、HONE-1、BM-1和AS-1) 中CXCR4表現是否會受到表觀遺傳 (epigenetic) 所調控。我們用甲基化特異性聚合酶鏈反應 (MSP) 確認CXCR4基因promoter甲基化狀況。結果發現只有AS1細胞CXCR4基因promoter上的CpG islands是未甲基化，其它三株細胞株都有高甲基化狀況。接著我們使用去甲基化藥物 (例如: 5-Aza-2’-deoxycytidine) 與組蛋白去乙醯化酶抑製劑 (例如: Trichostatin A)去處理4株鼻咽癌細胞株，之後利用定量real-time RT-PCR、免疫化學染色法與西式墨點法分析加藥後CXCR4 mRNA與蛋白的變化。我們發現藥物處理後細胞中的CXCR4 mRNA與蛋白表現量明顯增加，這些實驗結果證明在鼻咽癌細胞中CXCR4表現會受到表觀遺傳的調控。
第二部份
Twist過去被發現與許多癌症轉移有相關性，包括:肝癌、乳癌與前列腺癌，然而Twist在頭頸癌中所扮演的角色並不清楚。因而我們研究主要是探討Twist在頭頸癌中的表現及可能扮演的角色。我們首先利用CH1組織微陣列 (tissue microarray, TMA) (它含有50位頭頸癌病人的資料) 進行CXCR4、CXCR6、CCR7、Twist、E-cadherin、Fibronectin 與Osteopontin免疫組織化學染色，之後將染色結果與病人臨床資料進行統計分析，染色結果我們發現50位病人組織中Twist、CXCR4、CXCR6、CCR7、E-cadherin、Fibronectin與Osteopontin蛋白陽性率分別為20 (40.0%)、25 (50.0%)、25 (50.0%)、20 (40.0%)、25 (50.0%)、15 (30.0%)與36 (72.0%)。此外Twist表現也與病人腫瘤細胞分化狀況 (p= 0.027)，淋巴結轉移 (p= 0.032) 與疾病惡化程度 (p= 0.029) 都有正相關; 另外也發現CCR7與CXCR4表現與淋巴結轉移有正相關。利用Spearman統計分析顯示Twist的表現與CXCR4 (Spearman, r=0.408, p= 0.003) 和 CCR7 (r=0.417, p= 0.003) 表現有正相關。接著我們使用short hairpin RNA (sh-RNA)技術，降低頭頸癌細胞株 (HONE1) 內Twist的表現量，之後利用定量real-time RT-PCR、西式墨點法與免疫細胞化學染色法，分析HONE1細胞株內CXCR4與CCR7的m-RNA與蛋白表現量。結果發現降低HONE1細胞株內Twist的表現量，確實會使CXCR4與CCR7的m-RNA及蛋白表現量隨著下降。這個研究証實了，Twist (已知是轉錄因子) 可能藉由調控CXCR4與CCR7表現而幫助鱗狀細胞癌的腫瘤細胞轉移到淋巴結。

Part 1
Nasopharyngeal carcinoma is an epithelial cancer that metastasizes predictably to cervical lymph nodes or distant organs. To assess whether the chemokine receptors of NPC cells play important roles in metastasis and are associated with history of radiotherapy. We analyzed the significance of various chemokine receptors (CCR1-10, CXCR1-6, XCR1, and CX3CR1) in five NPC cell lines (TW01, TW04, HONE1, BM1, and AS1) and 52 NPC tumor biopsies from 48 NPC patients. We found that only CCR7, CCR9, CXCR4 and CXCR6 showed substantial amount of messenger RNA in these NPC cell lines. Quantitative real-time reverse transcription-PCR revealed that heterogeneous expression of CCR7, CCR9, CXCR4 and CXCR6 mRNA in above NPC cell lines, subsequent flow cytometric analysis, chemotaxis assay and actin polymerization assay indicated surface receptors CCR7, CXCR4 and CXCR6 were functional in NPC cells. Surprisingly, CCR9 protein was expressed in cytoplasm but not on membrane of the NPC cells. Negative immunoreactivity for CCR7, CXCR4, and CXCR6 was demonstrated in almost all nasopharyngeal (NP) specimens from patients with primary NPC (n = 12) and in those with regional metastatic NPC (n = 15). However, expression of two or three of these chemokine receptors was demonstrated in NP specimens from patients with liver metastasis. Strong positivity was demonstrated for all three of these chemokine receptors in almost all of the regional and distant metastasis specimens. Significant differences in the expression of CCR7, CXCR4, and CXCR6 were found between primary tumours and metastases (p < 0.001, p < 0.001, and p < 0.002, respectively). This observation was further confirmed by laser capture microdissection of freshly frozen tumours from primary (n = 5) and metastatic (n = 8) NPC sites (p = 0.05, 0.03, and 0.03 for CCR7, CXCR4, and CXCR6, respectively). In addition, significant differences in CXCR4 expression were demonstrated between de novo and post-radiotherapy groups (1/22 vs. 5/8; p < 0.003). It appears reasonable to conclude, therefore, that CCR7, CXCR4, and CXCR6 are expressed and active in human NPC metastases, while CXCR4 expression is associated with history of radiotherapy.
Furthermore, we investigated whether CXCR4 on NPC cells (TW01, HONE1, BM1, and AS1) were undergone epigenetic regulation. Then, methylation-specific PCR (MSP) was performed to confirm methylation status of CXCR4 gene promoter. We found that the 5’ CpG islands of CXCR4 gene was unmethylated in AS1 cells, whereas promoter hypermethylation was detected in 3 NPC cell lines. Finally, NPC Cells were treated with a histone deacetylase inhibitor (Trichostatin A) and a demethylating agent (5-Aza-2’-deoxycytidine). Then, quantitative real-time RT-PCR, immunohistochemistry, and Western blot analysis were used to assess CXCR4 mRNA and protein expression induced by TSA and 5-Aza in NPC cell lines. We found that CXCR4 expression was increased in NPC cell lines treated with TSA, or both TSA and 5-Aza. These findings demonstrated that epigenetic regulation of CXCR4 in NPC cell lines.
Part 2
Twist has been found to be correlated with metastasis in various cancers including hepatocarcinoma, breast and prostate cancers. However, the role of Twist in head and neck squamous carcinoma (HNSCC) remains unknown. The purpose of this study is to investigate the expression and possible role of Twist in HNSCC. We examined CH1 tissue microarrays (TMAs) which composed of tumors from 50 patients with head and neck tumor. Immunohistochemical (IHC) stain analysis of CXCR4, CXCR6, CCR7, Twist, E-cadherin, Fibronectin and Osteopontin were performed, and the relationship between the staining pattern and clinicopathological features were studied. Out of the 50 cases of head and neck cancer, 20 (40.0%), 25 (50.0%), 25 (50.0%), 20 (40.0%), 25 (50.0%), 15 (30.0%) and 36 (72.0%) showed positive staining in the tumors cells for the Twist, CXCR4, CXCR6, CCR7, E-cadherin, Fibronectin and Osteopontin proteins, respectively. Further, Twist expression was positively associated with differentiation status (p= 0.027), lymph node metastasis (p= 0.032) and disease progression (p= 0.029). Besides, CCR7 and CXCR4 expression were also associated with lymph node metastasis. Further analysis revealed that the expression of Twist was positively correlated with CXCR4 (Spearman, r=0.408, p= 0.003) and CCR7 (r=0.417, p= 0.003) in tissue microarray experiment. Furthermore, down-regulation of Twist through short hairpin RNA (sh-RNA) was prepared in head and neck squamous carcinoma HONE1 cells. Quantitative RT-PCR, Western blotting and Immunocytochemical staining analysis were used to evaluate the effect of Twist sh-RNA. We found that knockdown of Twist by short hairpin RNA (sh-RNA) in HONE1 cells showed decreased mRNA and protein expression of CXCR4 and CCR7. This study demonstrated that the transcription factor Twist could regulate the CXCR4 and CCR7 expression in squamous cell carcinoma, which might lead to lymph node metastasis potential.

口試委員會審定書………………………………………………………Ⅰ
誌謝………………………………………………………………………Ⅱ
總目錄………………………………………………………… …………1
圖目錄………………………………………………………… …………7
表目錄……………………………………………………………………10
縮寫表 ………………………………………………………… ………11
第一部份: 趨化素受體在鼻咽癌中表現之研究………………………12
中文摘要…………………………………………………………………13
英文摘要…………………………………………………………………15
第一章 序論………………………………………………… …………17
1-1 鼻咽癌流行病學與病原學…………………………………………17
1-2 鼻咽癌之病理分類與分期…………………………………………19
1-3 鼻咽癌臨床症狀……………………………………………………20
1-4 鼻咽癌治療 ……………………………………… ………………21
1-5 趨化素與趨化素受體: 結構與分類………………………………22
1-6 癌症轉移……………………………………………………………25
1-7 腫瘤細胞轉移和趨化素-趨化素受體之間作用之相關性…… …26
1-8 表觀遺傳學 (epigenetics) 調控基因表現………………… …26
1-9 本論文研究動機與實驗策略………………………………………29
1-10 本論文研究成果概述…………………………………… ………30
第二章 實驗材料與方法……………………………………… ………31
2-1 材料…………………………………………………………………31
2-1-1 儀器設備…………………………………………………………31
2-1-2 藥品………………………………………………………………32
2-1-3 試劑組……………………………………………………………34
2-1-4 抗體………………………………………………………………34
2-1-5 試劑配置…………………………………………………………35
2-1-6 人類鼻咽癌細胞株 (human NPC cell lines)……… ………39
2-2 方法…………………………………………………………………40
2-2-1 移形分析 (migration assay)…………………………………40
2-2-2 抽取RNA與反轉錄-聚合酶連鎖反應 (extraction of RNA and RT-PCR)…………………………………………… ……………40
2-2-3 即時定量聚合酶連鎖反應 (qantitative real-time PCR)…44
2-2-4 流式細胞儀分析 (flow cytometry analysis)………………45
2-2-5 趨化性分析 (chemotaxis assay)………………… …………46
2-2-6 肌動蛋白聚合檢测 (actin polymerization assay)… ……47
2-2-7 組織免疫化學染色抗體效價測定 (tissue immunohistochemistry antibody titration)………………………48
2-2-8 鼻咽癌病人檢體…………………………………………………49
2-2-9 鼻咽癌組織免疫化學染色 (Immunohistochemical stain of NPC tissues)……………………………………………………………49
2-2-10 雷射擷取顯微切割 (laser capture microdissection, LCM)........……………………………………………………………50
2-2-11 鼻咽癌細胞株處理5-Aza與TSA…………………… …………51
2-2-12 西式墨點法測定鼻咽癌細胞株 (western blot)……………52
2-2-13 免疫細胞化學染色測定鼻咽癌細胞株 (immunocytochemical stain)……………………………………………………………………53
2-2-14 甲基化特異性聚合酶連鎖反應 (methylation-specific PCR)……………………………………………………………………………55
2-2-15 增殖分析測定鼻咽癌細胞株 (proliferation assay)……………………………………………………………………………59
2-2-16 統計分析 (statistical analysis)……………………………………………………………………………59
第三章 實驗結果………… ……………………………………………60
3-1 胎牛血清與周邊血漿中，含有能吸引鼻咽癌細胞進行migration的物質……………………………………………………………………60
3-2 RT-PCR篩選目前已知18個趨化素受體在鼻咽癌細胞株中的表現…………………………………………………………………………60
3-3 Real-time PCR定量CCR7、CCR9、CXCR4 與CXCR6在鼻咽癌細胞株表現量……………………………………………………………………61
3-4 Flow cytometry分析CCR7、CCR9、CXCR4與CXCR6蛋白在鼻咽癌細胞中表現…………………………………………………………………61
3-5 CXCL16是否能引起帶有CXCR6細胞株具有細胞趨化能力…… …62
3-6 CXCL16是否能引起帶有CXCR6細胞株的actin polymerization62
3-7 Immunohistochemical stain評估CXCR4、CXCR6與CCR7在鼻咽癌組織表現…………………………………………………………………63
3-8 LCM-qRT-PCR評估在原發癌組織和轉移癌組織中CXCR4、CXCR6與CCR7 mRNA表現………….………………………………………………65
3-9 鼻咽癌細胞株處理5-Aza 與TSA觀察CXCR4 m-RNA表現…………65
3-10 鼻咽癌細胞株處理5-Aza 與TSA觀察CXCR4 蛋白表現…………66
3-11 利用methylation-specific PCR分析鼻咽癌細胞株中CXCR4基因的DNA甲基化狀況……………………………………………… ………66
第四章 討論………………………………… …………………………68
第五章 參考文獻………………………… ……………………………73
圖…………………………………………………………………………83
表……………………………………………………………… ………106
第二部份: Twist在頭頸癌中調控CXCR4與CCR7的研究………… …114
中文摘要…………………………………………………………… …115
英文摘要………………………………………………………… ……117
第一章 序論……………………………………………………………119
1-1 頭頸部鱗狀細胞癌……………………………………… ………119
1-2 Twist介紹…………………………………………………………120
1-3 腫瘤相關蛋白……………………………………………… ……121
1-4 本論文研究動機與實驗策略…………………………… ………124
1-5 本論文研究成果概述……………………………………… ……125
第二章 實驗材料與方法………………………………………………126
2-1 材料………………………………………………………… ……126
2-1-1 儀器設備………………………………………………… ……126
2-1-2 藥品…………………………………………………… ………126
2-1-3 試劑組…………………………………………………… ……126
2-1-4 抗體……………………………………………………… ……126
2-1-5 試劑配置………………………………………………… ……127
2-1-6 細胞株…………………………………………………… ……127
2-1-7 腫瘤組織微陣列 (tumor tissue arrays) …………………127
2-1-8 sh-RNA載體……………………………………………… ……127
2-2 方法……………………………………………………… ………128
2-2-1 免疫組織化學染色分析TMAs (Immunohistochemical staining of tissue microarrays)…………………………………128
2-2-2 利用sh-RNA技術，產生穩定sh-RNA-Twist HONE1細胞株….129
2-2-3 抽取RNA，進行定量real-time RT-PCR………………………129
2-2-4 西式墨點法測定HONE1細胞株 (western blot)…… ………130
2-2-5 免疫細胞化學染色測定HONE1細胞株 (immunocytochemical stain)………………………………………………………… ………130
2-2-6 增殖分析測定細胞株生長速度 (proliferation assay) …131
2-2-7 統計分析 (statistical analysis)…………………………131
第三章 實驗結果………………………………………………………133
3-1 利用免疫化學染色觀察CH1 TMAs中Twist、CXCR4、CXCR6、CCR7、E-cadherin、Fibronectin與Osteopontin蛋白的表現… …133
3-2 Twist、CXCR4與CCR7表現與淋巴結轉移有正相關; 而Pairwise相關性統計分析更發現三者有相關性存在 ……………………………133
3-3 sh-RNA-Twist減低HONE1細胞內Twist表現，也造成CXCR4與CCR7表現減少……………………………………………………… ………134
3-4 CCR7與CXCR4基因啟動子區域，有E-box序列可與Twist結合..136
第四章 討論……………………………………………………………138
第五章 參考文獻………………………………………………………140
圖…………………………………………………………… …………146
表…………………………………………………………… …………156
附錄A 第一部份已發表之文章……………………………………… 161
附錄B 第二部份正在投搞之文章…………………………………… 172

Part 1

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