2011-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/648974摘要：大腸直腸癌為世界上第二大癌症死亡原因；在台灣，大腸直腸癌的發病率逐年增加，每年約有一萬個新增病例，四千人因此疾病死亡。雖然近年來，不斷有新的治療方式或藥物被研發用以治療大腸直腸癌，但是針對進展性的大腸直腸癌，這些個別的治療方式或是整合性的治療方式，均無法完全將其治癒。這個狀況有可能是因為目前的治療藥物，並未確實作用在引起腫瘤生長的分子機轉或是細胞族群。癌起始細胞的觀念在近年來逐漸被癌症研究者接受，此觀念主要是指在腫瘤中，只有一小部分具有幹細胞特性的癌細胞，能引起腫瘤的生長及轉移。然而在大腸直腸癌中，此族群細胞的標誌或使其和臨床治療預後的關係皆未被清楚的了解與闡釋。G9a 為哺乳動物的組蛋白甲基轉移酶，負責催化組蛋白H3 上第九個離胺酸 (K9) 的甲基化，組蛋白H3K9的甲基化對腫瘤抑制基因 (tumor suppressor gene) 轉錄的抑制扮演關鍵性的角色。先前研究指出，G9a 在胚胎幹細胞中藉由抑制Oct3/4 扮演調控分化的角色;在癌症研究方面，已知在缺氧的情形下，會誘發G9a 表現及增加其甲基轉移酶活性進而調控基因表現。在乳癌細胞中，G9a 也被發現可降低腫瘤抑制基因的表現，除此之外，目前對於G9a 在癌症上扮演的角色仍不甚清楚。先前本實驗室研究發現 G9a 高度表現在不同類型癌症病人的腫瘤組織中，其中包括大腸癌。至今G9a 在大腸直腸癌進程與大腸癌起始細胞中是否扮演的重要關鍵角色目前尚未知。因此本研究計畫以下列三項目標：(1)確立G9a 在大腸直腸癌進程及在大腸癌起始細胞中扮演的生物功能角色; (2)確立G9a 藉由表基因調控影響大腸癌起始細胞的分子機制; (3)確立G9a 與大腸癌起始細胞在大腸直腸癌病臨床的重要性。我們希望藉由研究大腸癌起始細胞這個有如大腸直腸癌阿基里斯鍵的關鍵角色，點亮醫學界對癌症起始細胞的了解，找到新的癌症治療藥物或方法，往治癒癌症的目標前進。<br> Abstract: Colorectal cancer (CRC) is the second leading cause of death from cancer in the UnitedStates. In Taiwan, CRC is the third leading cause of death from cancer, with nearly 10000new cases and 4000 deaths per year. It is gradually accepted that only a small fraction ofcancer cells with the property of stem cells, known as cancer-initiating cells (CICs), areresponsible for tumor growth and metastasis. However, little is known of the translationaland basic research efforts of colon cancer-initiating cells (CCICs) in human CRC. Thus,investigating the molecular mechanisms controlling CCICs regulation will shed new light inthe treatment and diagnosis of colon cancer. SET domain-containing protein, G9a, is a novellysine-preferring mammalian histone methyltransferase that responsible for the majority ofeuchromatic histone H3 lysine 9 methylation. Current evidence suggests that G9acontributes to the epigenetic silencing of tumor suppressor genes and maintain the malignantphenotype. Overexpression of G9a, essential in stem cell differentiation, has been linked tomediate irreverseible epigenetic inactivation of OCT-3/4 during early embryogenesis.However, critical mechanism linking increased G9a expression to cancer-initiating cellregulation and cancer progression remains largely unknown. Our Subproject proposal aimsare to (1) To define the biological function of G9a in CCICs and colon cancerprogression, (2) To determine the epigenetic regulations and molecular mechanismsinvolving the regulation of CCCIs by G9a, (3) To examine the clinical significance ofG9a, CCICs and candidate genes in patients. We hope our work into this “ cancer’sAchilles Heel” of colorectal cancer will not sheet light on an important role of G9a in CRCprogression, but also provide a possible new target for drug development progression.大腸直腸癌大腸癌起始細胞組蛋白甲基轉移酶CRCCCICsG9a