2014-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/644489摘要：本計劃的目標是研究黏液蛋白醣化酶 GALNT1 與肝細胞癌在臨床病理的關連性與探討其參與在肝細胞癌的致病機轉。肝細胞癌的發生率在全球癌症罹患率排名為第三，而台灣每年有 8,000個新病例，並且每年高達 7,000 人死於肝細胞癌，是一個高致死率的癌症。黏液蛋白醣化酶 GALNT1 是 GALNT家族的廿個成員之一。相較 GALNT 家族廿個成員，其表現在跨物種中為高度保留的基因。GALNT的功能為於黏液蛋白醣化作用過程中自 UDP-GalNAc 轉移 GalNAc醣至醣蛋白，催化黏液醣蛋白結構形成的第一個步驟。許多文獻發現，此種單醣蛋白結構普遍地發生於癌化的細胞表面，包括乳癌與大腸癌細胞，並且與細胞癌化與發展扮演著重要的角色。在肝臟 GALNT1 是最主要表現的黏液蛋白醣化酶，然而過去對於 GALNT1的功能及其醣化作用參與在肝細胞癌化機轉的研究卻鮮少被研究。從公開的資料庫檢索分析與我們的初步實驗結果都顯示，GALNT1 mRNA與蛋白質在肝細胞癌組織中有大表現量，並且高表現量的 GALNT1腫瘤組織與病人的存活率下降有統計上的關聯性。在細胞實驗結果顯示 GALNT1 可以調控肝癌細胞的惡性行為特性，此外經由 EGF 刺激可以誘發肝癌細胞的轉移與侵入之特性。因此，我們推論 GALNT1 在肝細胞癌疾病發展與癌化機轉中扮演著重要的角色。本研究計畫目標為：1. 分析肝細胞癌組織中 GALNT1 mRNA與蛋白質的表現量與臨床病理的關連性。2. 從 in vivo 和 in vitro實驗探討 GALNT1調控肝細胞癌惡性行為之特性。3. 研究 GALNT1 參與在肝細胞癌惡性行為中之調控機轉。4. 探討 GALNT1 與目前肝細胞癌標把藥物作用調控機制。本研究將建立黏液蛋白醣化酶 GALNT1 在肝細胞癌疾病發展過程中的角色。更重要的是，我們將可以發現黏液蛋白醣化酶在肝癌診斷、預後、以及作為標把藥物的潛力。未來可望提供肝細胞癌藥物開發與診斷試劑之研發。<br> Abstract: The objective of this study is to establish the correlation between GALNT1 expression and HCC clinicopathological characteristics and to investigate the role of GALNT1 in HCC pathogenesis. HCC is a highly lethal cancer being the third most frequent cause of cancer-related death worldwide with approximately 8000 new cases diagnosed and 7000 deaths occurring annually in Taiwan. N-acetylgalactosaminyl- transferase 1 (GALNT1) is a member of a large polypeptide N-acetylgalactosamine (GalNAc)-transferase (GALNT) family that catalyzes the first step in the biosynthesis of mucin-type O-glycosylation. GALNT1 is a highly conserved and the major GALNT enzymes expressed in liver. However, very few studies have reported the function of GALNT1 in cancer and none on the role of GALNT1 O-glycosylation in HCC development. Public database and our preliminary data show that GALNT1 mRNA and protein is frequently up-regulated in HCC and tumours expressing higher levels of GALNT1 are associated with poor overall survival. In vitro studies reveal GALNT1 expression regulates HCC cell malignant behaviours and EGF-induced migration and invasion. Thus we hypothesise that GALNT1 expression play critical roles in the pathogenesis and disease progression of HCC. The aims of this study are, 1. To determine the correlation between GALNT1 expression and HCC clinicopathological characteristics. 2. To investigate the effects of GALNT1 on HCC malignant phenotypes in vitro and in vivo. 3. To verify the target of GALNT1 and the underlying mechanism affecting HCC malignant phenotypes. 4. To determine the role of GALNT1 in HCC targeted drug therapy. Understanding the effects of GALNT1 in HCC pathogenesis will aid in the knowledge buildup on the role of GALNT1 in O-glycosylation and disease progression and render the potential as a target for therapeutic drug development.