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研究生:楊嘉欣
研究生(外文):Jia-Sin Yang
論文名稱:碳酸酐酶IX與口腔癌致癌機轉之探討
論文名稱(外文):The Study of the Mechanisms of Carbonic Anhydrase IX in Oral Cancer Carcinogenesis
指導教授:楊順發謝易修謝易修引用關係
學位類別:博士
校院名稱:中山醫學大學
系所名稱: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:2013
畢業學年度:101
語文別:中文
論文頁數:124
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口腔癌 (oral cancer) 是臺灣地區發生率和死亡率增加速度最快之癌症,因其屬於固態惡性腫瘤所以易伴隨缺氧情形的發生,而碳酸酐酶 IX (carbonic anhydrase IX; CAIX) 為缺氧時易誘發產生的蛋白,且高度表現於多種人類癌症中,然而,CAIX 與臺灣口腔癌的相關性目前仍尚未釐清,因此,本研究探討 CAIX 在臨床檢體上的表現與臨床病理參數間之相關性,並進一步以細胞實驗探究 CAIX 在口腔癌的分子機轉中所扮演的角色。首先以酵素連結免疫吸附法 (enzyme-linked immunosorbent assay; ELISA) 分析 100 名健康對照者、30 名口腔黏膜下纖維化 (oral submucosal fibrosis; OSF) 患者及 191 名口腔癌患者血漿中 CAIX 的濃度,結果顯示口腔癌患者 (p<0.001) 或口腔黏膜下纖維化患者 (p<0.001) 的 CAIX 表現量顯著高於健康對照者,而口腔癌患者血漿中 CAIX 的表現量與年齡 (p<0.05)、嚼食檳榔 (p<0.05)、腫瘤大小 (p<0.05) 和腫瘤分期 (p<0.05) 呈現正相關。接著以免疫組織化學染色法 (immunohistochemistry; IHC) 分析 259 個口腔癌組織中 CAIX 的表現量,結果發現口腔癌患者組織中 CAIX 的表現量與遠端轉移 (p<0.05) 和腫瘤分期 (p<0.05) 呈現正相關。進一步篩選了穩定過度表現 CAIX 的 SCC-9 人類口腔癌細胞株進行研究,由傷口癒合試驗 (wound healing assay) 和 Boyden chamber assay 的結果發現 CAIX 大量表現會提升 SCC-9 細胞的移動和侵襲能力,接著利用反轉錄聚合酶連鎖反應 (reverse transcription- polymerase chain reaction; RT-PCR)、即時定量聚合酶連鎖反應 (real-time PCR) 和西方墨點法 (western blot) 的實驗結果發現 CAIX 大量表現會增加基質金屬蛋白水解酶-9 (matrix metalloproteinases-9; MMP-9) 的 mRNA 和蛋白表現量、訊息傳遞蛋白黏著斑激酶 (focal adhesion kinase; FAK)、類固醇受體輔激活蛋白 (steroid receptor coactivator; Src) 和細胞外訊息調節激酶1/2 (extracellular signal-regulated kinase 1/2; ERK1/2) 的磷酸化表現量、以及轉錄因子核內因子-κB (nuclear factor-κB; NF-κB)、c-Jun 和 c-Fos 的核蛋白表現量,再利用螢光素酶報導基因試驗 (luciferase reporter gene assay) 和染色質免疫沈澱試驗 (chromatin immunoprecipitation assay; ChIP assay) 的實驗結果發現 CAIX 大量表現會增加 NF-κB、c-Jun 和 c-Fos 與 MMP-9 基因啟動子上 NF-κB 和活化蛋白-1 (activator protein-1; AP-1) 接合區的結合能力。由臨床檢體結果推論 CAIX 的表現可作為ㄧ生物標記來預測口腔癌的病程,而細胞實驗也證實 CAIX 大量表現會增加 FAK、Src 和 ERK1/2 的磷酸化,進而促進 NF-κB、c-Jun 和 c-Fos 等轉錄因子轉位進入細胞核內,與 MMP-9 基因啟動子上的 NF-κB 和 AP-1 接合區結合,使 MMP-9 的 mRNA 和蛋白表現增加,促進口腔癌細胞的轉移。

Oral cancer has the fastest growing incidence and mortality rates among all cancer types in Taiwan. Oral cancer is a solid malignant tumor that is prone to occur following hypoxia. Carbonic anhydrase IX (CAIX), which is a hypoxia-induced transmembrane protein, is highly expressed in various forms of cancer. However, the correlation between CAIX and the incidence of oral cancer in Taiwan has not been clarified. In this study, we examined the expression of CAIX in clinical specimens, and used the results to determine the correlation between CAIX and clinicopathological parameters. In addition, we conducted cell experiments to investigate the role of CAIX in the molecular mechanisms of oral cancer. First, we used an enzyme-linked immunosorbent assay (ELISA) to determine the plasma CAIX concentrations of 100 healthy control participants, 30 patients diagnosed with oral submucosal fibrosis (OSF), and 191 oral cancer patients. The results indicated that the CAIX expression in the oral cancer patients (p<0.001) and OSF patients (p<0.001) were substantially higher than that of the healthy participants, and the plasma CAIX levels of oral cancer patients were positively correlated to patient age (p<0.05), history of chewing areca nuts (p<0.05), tumor size (p<0.05), and tumor stage (p<0.05). We then performed an immunohistochemistry (IHC) test to analyze the CAIX expression in 259 oral cancer tissue specimens. The results indicated that the CAIX expression in oral cancer tissue was positively correlated to distant metastasis (p<0.05) and tumor stage (p<0.05). Subsequently, we conducted a wound healing assay and a Boyden chamber assay to examine an SCC-9 human oral cancer cell line, which consistently overexpresses CAIX. The results indicated that the overexpression of CAIX increases the movement and invasion capacity of SCC-9 cells. In addition, we performed reverse transcription-polymerase chain reaction (RT-PCR), real-time PCR, and western blot tests and found that CAIX overexpression increases the mRNA and protein expressions of matrix metalloproteinases-9 (MMP-9), phosphorylation expression in the focal adhesion kinase (FAK), steroid receptor coactivator (Src), and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling proteins, and nucleoprotein expression in transcription factors nuclear factor-κB (NF-κB), c-Jun, and c-Fos. We also performed a luciferase reporter gene assay and a chromatin immunoprecipitation (ChIP) assay and found that CAIX overexpression increases the binding capacity of NF-κB, c-Jun, and c-Fos regarding the NF-κB and activator protein-1(AP-1) binding sites on the MMP-9 gene promoter. According to the results obtained from the clinical specimens, we inferred that CAIX expression can be used as a biomarker to predict the course of oral cancer. In addition, the cell experiments confirmed that the overexpression of CAIX increases the phosphorylation of FAK, Src, and ERK1/2, thereby enabling transcription factors NF-κB, c-Jun, and c-Fos to translocate and enter the nucleus, binding to the NF-κB and AP-1 binding sites on the MMP-9 gene promoter. This reaction increases the mRNA and protein expressions of MMP-9, which consequently induces the metastasis of oral cancer cells.

致謝.......................................................I
摘要.....................................................III
Abstract...................................................V
目錄....................................................VIII
縮寫表....................................................XI
第一章 緒論................................................1
1. 口腔癌...........................................2
2. 碳酸酐酶 IX......................................5
3. 腫瘤生成與轉移..................................10
4. 基質金屬蛋白水解酶..............................12
5. 訊息傳遞路徑....................................16
6. 研究動機與目的..................................24
第二章 材料與方法.........................................26
1. 研究族群及檢體來源..............................27
2. 酵素連結免疫吸附法..............................29
3. 免疫組織化學染色法..............................30
4. 細胞培養........................................31
5. 蛋白質分析......................................36
6. RNA 分析........................................40
7. 質體製備........................................45
8. 質體轉染........................................49
9. 建立穩定轉染細胞株..............................51
10. 體外腫瘤轉移試驗................................52
11. 螢光素酶報導基因試驗............................54
12. 染色質免疫沈澱試驗..............................55
13. 統計分析........................................58
第三章 結果...............................................59
1. 健康對照者、口腔黏膜下纖維化患者與口腔癌患者其血液檢體之臨床資料............................................60
2. 健康對照者、口腔黏膜下纖維化患者與口腔癌患者其血液檢體之 CAIX 的表現量......................................61
3. 血液檢體其 CAIX 的表現量對於口腔癌診斷之準確性評估........................................................61
4. 口腔癌患者其血液檢體之 CAIX 表現量與臨床病理參數的相關性....................................................61
5. 口腔癌患者其組織檢體之臨床資料..................62
6. 口腔癌患者其組織檢體之 CAIX 表現量與臨床病理參數之相關性....................................................63
7. 不同人類口腔癌細胞株其 CAIX 表現量之分析........64
8. 建立穩定過度表現 CAIX 重組質體的 SCC-9 人類口腔癌細胞株....................................................64
9. 穩定過度表現 CAIX 重組質體的 SCC-9 人類口腔癌細胞株其轉移能力之影響........................................65
10. 穩定過度表現 CAIX 重組質體的 SCC-9 人類口腔癌細胞株其 MMPs 家族表現量之分析................................66
11. 穩定過度表現 CAIX 重組質體的 SCC-9 人類口腔癌細胞株其 MMP-9 表現量之分析...................................66
12. 利用 MMP-9 shRNA 轉染穩定過度表現 CAIX 重組質體的 SCC-9 人類口腔癌細胞株其 MMP-9 表現量與轉移能力之影響.....67
13. 利用 MMPs 抑制劑 GM6001 處理穩定過度表現 CAIX 重組質體的 SCC-9 人類口腔癌細胞株其 MMP-9 表現量與轉移能力之影響........................................................67
14. 穩定過度表現 CAIX 重組質體的 SCC-9 人類口腔癌細胞株其 FAK/Src 訊息傳遞蛋白表現量之分析.....................68
15. 利用 FAK Y397F 突變體轉染穩定過度表現 CAIX 重組質體的 SCC-9 人類口腔癌細胞株其 FAK 及 MMP-9 表現量與轉移能力之影響....................................................69
16. 穩定過度表現 CAIX 重組質體的 SCC-9 人類口腔癌細胞株其 MAPK 及 PI3K/Akt 訊息傳遞蛋白表現量之分析............69
17. 利用 MEK1/2 抑制劑 U0126 處理穩定過度表現 CAIX 重組質體的 SCC-9 人類口腔癌細胞株其 ERK1/2 及 MMP-9 表現量與轉移能力之影響..............................................70
18. 穩定過度表現 CAIX 重組質體的 SCC-9 人類口腔癌細胞株對其 MMP-9 基因上啟動子之影響...........................71
19. 穩定過度表現 CAIX 重組質體的 SCC-9 人類口腔癌細胞株對其轉錄因子 NF-κB、c-Jun 和 c-Fos 在細胞核內蛋白表現之影響........................................................72
20. 穩定過度表現 CAIX 重組質體的 SCC-9 人類口腔癌細胞株其轉錄因子 NF-κB 及 AP-1 與 MMP-9 基因啟動子結合能力之影響........................................................73
第四章 討論...............................................74
參考文獻..................................................80
圖表與圖表說明............................................99
已發表之論文.............................................123


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