2015-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/658282摘要：頭頸部鱗狀細胞癌是全世界第六大癌症，也是台灣男性癌症第四大死因。即使過去數十年頭頸癌治療有大幅進步，但過程中癌細胞對於化療藥物產生抗性，進而導致癌症復發、轉移仍然是治療上的最大難題。而抗藥性之產生被認為與癌細胞惡性程度有關。研究已知，表觀基因修飾異常為癌症發生與惡化之重要機制，其中負責催化組蛋白 H3上第九個離胺酸位點甲基化之組蛋白甲基轉移酶 G9a，在抑制抑癌基因轉錄及促進癌症進程中扮演關鍵角色。本實驗室發現 G9a會高度表現在頭頸癌病人之腫瘤組織，且與不良預後有高度相關；並在利用干擾性核醣核酸抑制 G9a 表現或以其專一性抑制劑bix-01294 阻斷活性後，會降低頭頸癌細胞之群落生成能力，顯示 G9a 能參與調控腫瘤的生成。且我們近來發現參與腫瘤對化療藥物 cisplatin 和 5Fu敏感性之調節。因此我們提出一假設：G9a在頭頸癌中不僅影響腫瘤發展，對於化療藥物之抗藥性也扮演關鍵角色。本研究計畫欲以下列三項目標，釐清 G9a在癌細胞中對化學治療之抗藥性的作用機制。並期望三項目標可幫助釐清癌症在生成化療藥物抗藥性時 G9a的角色與其中詳細的作用機轉，並希望此機制能提供日後癌症治療新標的之開發，以達到抑制腫瘤形成並增進化療藥物效力。 1. 釐清在頭頸部鱗狀細胞癌中 G9a調節化療藥物敏感性與抗藥性之角色； 2. 確認 G9a在化學治療抗藥性中調控的分子機制； 3. 利用動物實驗確立 G9a 調節抗藥性之特性，評估給予化療藥物合併抑制 G9a之治療效率，並建立 G9a在調控化療抗性之臨床重要性。 <br> Abstract: Epigenetic changes in tumors are associated not only with cancer development and progression but also with the chemotherapy resistance. Although there have been substantial advances in current chemotherapeutic strategies of head and neck squamous cell carcinomas (HNSCC), clinical drug resistance remains a major obstacle to achieve the successful cancer treatment and is still a limiting factor in patient survival. It is widely recognized that a wide variety of epigenetic changes are prevalent in cancer, including histone modification. Current evidences suggest that histone methyltransferase G9a, which is responsible for histone 3 lysine 9 methylation, contributes to promoting cancer cells malignancy. Additionally, previous studies and our preliminary data find that high expression of G9a has been linked to aggressiveness and poor prognosis of different cancer types including HNSCC. Furthermore, we also demonstrate that G9a is particularly crucial in regulating the sensitivity of cisplatin and 5-Fu in HNSCC. Therefore, we raise the hypothesis that G9a may be a linkage between HNSCC progression and drug resistance. In order to investigating the hypothesis, in this project, we will identify the chemo-sensitization mechanism mediated by G9a and the impacts on tumor behaviors. These findings will help us to understand the novel biological function of G9a, and may also prompt us to develop more effective approaches to adjuvant therapy of cancer. To deeply investigate this regulatory mechanism, the following specific aims are proposed, Specific aim 1: To investigate the role of G9a in regulation of chemotherapeutic drugs sensitivity and resistance in HNSCC. Specific aim 2: To validate the molecular mechanism regulated by G9a in chemotherapy resistance. Specific aim 3: To verify the clinical significance and evaluate the feasibility of combination therapy by animal model.化學治療抗藥性頭頸部鱗狀細胞癌G9a組蛋白 H3K9 甲基化chemotherapy resistancehead and neck squamous cell carcinomaG9aH3K9 methylation