2011-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/658292摘要：咽喉鱗狀上皮細胞癌是最常見的頭頸部癌症之一，據統計，此類癌症患者5年存活率低於 50％，因此如何延長病患存活率為一重要的全球健康問題。癌症的形成往往是由於關鍵基因突變導致正常的細胞繁衍失衡。除了DNA鹼基序列發生突變外，表觀遺傳修飾亦在參與調控基因的表現中扮演重要角色，其會在特定組蛋白殘基上透過不同的共價鍵修飾作用調控基因的轉錄。研究已知在胚胎發育與癌症發生過程中，組蛋白H3上第九個胺基酸離胺酸 (Lysine 9)的甲基化對於基因的表現與否扮演關鍵性的角色。研究已知組蛋白甲基轉移酶G9a負責催化組蛋白H3K9之甲基化。G9a會透過組蛋白H3K9的甲基化進而抑制某些抑癌基因的轉錄，研究顯示在缺氧的情形下G9a的表現及H3K9的甲基化皆會增加，進而調控基因的轉錄，此外，在肺癌與攝護腺癌的相關研究中也指出G9a扮演維繫腫瘤惡化的角色。先前本實驗室亦發現在頭頸部癌症病人癌組織中 G9a表現較正常組之高，且抑制頭頸部癌症細胞株之G9a表現初步發現細胞會產生類似自噬現象 (autophagy)之情況。但G9a在頭頸癌症發生過程中，作用機制目前尚未明瞭。因此，我們企圖探討G9a在頭頸部癌症發展過程中的重要性、調控機轉、細胞自噬及病人癒後之關聯性，期望藉此開發出有效治療癌症、以G9a做為標靶的抗癌策略。<br> Abstract: Squamous cell carcinoma of the larynx and hypopharynx is one of the most common head and neck squamous cell carcinoma (HNSCC). HNSCC represents a major worldwide health problem with patients exhibiting a 5-year survival rate lower than 50%. Tumorigenesis is considered to progress through a multistep process from normal histologic features to carcinoma features underlying genetic instabilities including the loss of heterozygocity (LOH) of certain chromosomes and the mutations of certain key genes. Epigenetic was later defined as heritable changes in gene expression that are not due to any alteration in the DNA sequence. Methylation of specific histone residues has important regulatory functions in chromatin organization and gene transcription, which have been linked to the silencing of a number of critical tumor suppressor genes during tumor formation. G9a is a histone methyltransferase (HMTase) for histone H3 lysine 9 dimethylation (H3K9me2), and it was reported that G9a-mediated H3K9me2 aberrantly repressed tumor suppressor genes in lung cancer and prostate cancer. In addition, in our previous approaches, we found that G9a expression was also highly expressed in HNSCC patients tumor tissues than normal parts. In our preliminary data, we demonstrated that downregulation of G9a markedly inhibits cell growth in colon cancer and HNSCC. Morevoer, after inhibition of G9a expression in HNSCC cells, there existed an autophagy-like phenomena in cells. However, mechanistic understanding of G9a’s role in cancer progression remains largely unknown. Therefore, we are interested in understanding its underlying molecular mechanisms of G9a in HNSCC. We would also like to investigate the correlation between G9a expression, autophagy and prognosis, which may serve as a potent therapeutic target. In our study, we will evaluate the role of G9a in tumor growth together with the G9a enzymatic activity inhibitor BIX-01294 in HNSCC.頭頸癌組蛋白甲基轉移酶細胞生長細胞自噬Head and neck squamous cell carcinoma (HNSCC)G9acell growthautophagy