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研究生:鄭傑文
研究生(外文):Chieh-Wen Cheng
論文名稱:以吲哚胺 2,3-雙氧化酶作為標靶的癌症免疫逃脫之研究
論文名稱(外文):Cancer Immune Escape Research on Targeting Indoleamine 2,3-dioxygenase
指導教授:高振益高振益引用關係
指導教授(外文):Jung-Yie Kao
口試委員:何其儻曹昌堯林振文
口試日期:2011-06-21
學位類別:博士
校院名稱:國立中興大學
系所名稱:生物化學研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2011
畢業學年度:99
語文別:中文
論文頁數:82
中文關鍵詞:
外文關鍵詞:immune escapeIDOHER2EGCG
相關次數:
  • 被引用被引用:1
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免疫逃脫是癌症發展過程中的一個重要特徵,但其詳細的分子機轉至今仍尚未清楚,丙型干擾素(IFN-γ)可誘發免疫細胞產生調控免疫的蛋白吲哚胺 2,3-雙氧化酶(IDO),這些免疫細胞與腫瘤細胞合作後,創造出利於癌細胞免疫逃脫的微環境。先前的研究指出IDO具有的免疫耐受性被發現與腫瘤初始成型有很大的相關性,IDO藉由降低局部區域的色胺酸而抑制T細胞增生且引發T細胞凋亡,因此抑制了T細胞的反應。另外已知第二型人類表皮生長因子受體(HER2)與癌症患者預後不佳有關,其中包括腫瘤的增生、侵襲與轉移。本研究發現,HER2在基因轉錄層面誘發IDO表現,且誘發的機制主要是透過Ras/MAPK訊息傳遞路徑,而HER2過度表現的癌細胞也會增加T細胞的細胞凋亡程度。此外,本研究也發現了綠茶萃取物中的主要化合物(-)-Epigallocatechin-3-gallate (EGCG)在轉錄層面上能抑制IFN-γ誘發口腔癌細胞IDO的表現,接著發現IFN-γ刺激活化口腔癌細胞的STAT1進而誘發IDO的生成,進一步的結果顯示EGCG可抑制IFN-γ刺激導致的STAT1蛋白上的酪胺酸與絲胺酸兩處的磷酸化,進而阻斷STAT1進入細胞核。此外,本研究更確認了IFN-γ刺激的口腔癌細胞中STAT1上游因子JAK1與JAK2的磷酸化皆可被EGCG所抑制。綜合以上結果顯示EGCG可藉由阻斷IFN-γ誘導的JAK-PKC-δ-STAT1訊息傳遞路徑而抑制IDO的基因表現。本論文首次提出HER2與IDO之間的關聯性,說明了HER2在癌症免疫逃脫中扮演的角色;另一部分指出EGCG可增強免疫能力與癌症治療的機制與效果,此結果同時也說明了在癌症的免疫與標靶治療方面,EGCG是一個具有潛力的藥物。

Immune escape is a characteristic of cancer progression, but its underlying molecular mechanism remains poorly understood. Indoleamide 2,3-dioxygenase (IDO), an immunomodulatory protein which is induced by gamma-interferon (IFN-gamma in several immune cells appearing in cancer cell microenvironment, can enhance immune escape. Previous studies show that IDO is expressed in the process of tumor formation and associated with cancer cell immune tolerance. By locally degrading tryptophan, IDO inhibits the proliferation of T lymphocytes and induces T cell apoptosis leading to suppression of T cell response. Human epithelial growth factor receptor 2 (HER2 or ErbB2) is known to be associated with a poor clinical outcome, including tumor progression and cancer metastasis. This study reveals that HER2 induces IDO expression at the transcriptional level through Ras/MAPK pathway leading to enhancement of T cell apoptosis. Additionally, (-)-epigallocatechin-3-gallate (EGCG), the major constituent of green tea, is found to significantly inhibit the expression of IDO at transcriptional level in human oral cancer cells. Activation of STAT1 is discovered to play an important role in regulation of IDO expression induced by IFN-gamma. This study demonstrates that EGCG is able to inhibit the translocation of STAT1 into nucleus in IFN-gamma-stimulated human oral cancer cells. In addition, this study elucidates that phosphorylation of both Tyr 701 and Ser 727 on STAT1 is also suppressed by EGCG. Moreover, phosphorylation of JAK-1 and JAK-2 which are the upstream event for the activation of STAT1 are also inhibited by EGCG in IFN-gamma-stimulated human oral cancer cells. These data indicate that EGCG inhibits IDO expression by blocking IFN-gamma-induced JAK-PKC-δ-STAT1 signaling pathway. Taken together, this study provides crucial evidence of a relationship between HER2 and IDO and reveals that EGCG is a potential drug for immune and target therapy to enhance cancer therapy via increasing antitumor immunity.

謝 誌 I
中文摘要 III
英文摘要 IV
目 次 VI
縮寫表 VIII
第一章 緒論 1
第一節 緣起 1
第二節 吲哚胺 2,3-雙氧化酶 5
一、IDO蛋白的功能與結構 5
二、IDO生合成的調控路徑 7
三、IDO引發免疫耐受性和癌症之間的關係 8
第三節 人類表皮生長因子受體第二型 11
一、HER2的功能與結構 11
二、HER2的訊息傳遞路徑 13
三、HER2與癌症惡性度的關係 15
第四節 綠茶與兒茶素的抗癌背景研究 17
第五節 研究動機與目的 19
第二章 材料與方法 20
第一節 藥品與試劑 20
第二節 主要器材與儀器 24
第三節 細胞株 25
第四節 實驗方法 26
一、細胞培養 26
二、西方墨點法 26
三、免疫螢光染色 26
四、細胞總量RNA的抽取 27
五、反轉錄聚合酶連鎖反應 27
六、質體純化 27
七、質體的構築 28
八、大腸桿菌之轉型 28
九、DNA轉染 28
十、冷光測試啟動子活性 29
十一、T細胞分離與培養 29
十二、Annexin V染色 30
十三、高效液相層析法 30
十四、IDO啟動子刪除突變(deletion mutation)試驗 30
十五、統計分析 31
第三章 結果 32
第一節 HER2藉由提高吲哚胺 2,3-雙氧化酶表現進而促進癌細胞之免疫逃脫 32
一、HER2與IDO的表現呈正相關 32
二、HER2可增強細胞中免疫調控蛋白IDO的表現 32
三、核醣核酸干擾技術降低HER2表現引發細胞中IDO表現亮減少 33
四、HER2於基因轉錄層面又發IDO的表現 34
五、HER2經由Ras/MAPK訊息傳遞路徑誘發IDO基因轉錄 34
六、HER2過度表現後增強乳癌細胞又發T細胞凋亡 36
第二節 EGCG藉由阻斷丙型干擾素誘發的訊息傳遞進而抑制口腔癌細胞中吲哚胺 2,3-雙氧化酶表現 37
一、EGCG促使口腔癌細胞中IDO的表現量降低 37
二、EGCG抑制IDO的表現於轉錄層面 37
三、EGCG抑制丙型干擾素誘發口腔癌細胞的IDO表現 39
四、HSC-3細胞中丙型干擾素透過JAK-STAT路徑誘發IDO表現 39
五、EGCG阻斷丙型干擾素誘使HSC-3細胞的STAT1聚集在細胞核中 39
六、EGCG能抑制丙型干擾素刺激後所引發的JAK1/2 以及PKC-δ活化STAT1 40
第四章 討論 42
第五章 結論 49
第六章 參考文獻 50
圖表 59
附錄 81

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