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標題: | SIRT1在肝癌中過度表現並促進其癌化現象和抗藥性 SIRT1 overexpression in hepatocellular carcinoma promotes tumorigenesis and resistance to chemotherapy |
作者: | Hsieh-Cheng Chen 陳協成 |
指導教授: | 鄭永銘 |
關鍵字: | 肝癌,癌化現象,SIRT1,ubiquitin和ALDH1A1, hepatocellular carcinoma,tumorigenesis,SIRT1,ubiquitin and ALDH1A1, |
出版年 : | 2011 |
學位: | 碩士 |
摘要: | SIRT1是一個依賴菸鹼腺嘌呤雙核苷酸催化的去乙醯酵素,它在許多生物功能扮演重要的角色,包括對壓力的回應、凋亡、細胞內代謝機制、卡路里限制的適應、老化和癌化現象。我們發現SIRT1蛋白在肝癌中有過度表現的現象。SIRT1表現量多的樣本其腫瘤分級較高、腫瘤分期較晚期並且病人預後較差。SIRT1蛋白量上升並不是因為SIRT1 mRNA的上升。SIRT1蛋白表現量較高的肝癌細胞株其SIRT1蛋白半衰期較長。我們進而證實SIRT1的降解是經由依賴ubiquitin方式之26S蛋白酶的作用。SIRT1的過度表現會促進癌化現象和抵抗化學治療藥物的效力。此外,我們找到ㄧ些可能為SIRT1新標靶的蛋白質,包括視網膜脫氫酶1、核磷酸蛋白、熱休克同源蛋白71、熱休克蛋白60、異質核的核醣核蛋白K和異質核的核醣核蛋白H。我們發現抑制SIRT1活性會減少ALDH1酵素活性。 SIRT1 is a NAD+-dependent deacetylase that plays crucial roles in many biological processes, including stress response, apoptosis, cellular metabolism, adaptation to calorie restriction, aging, and tumorigenesis. We find that SIRT1 protein is overexpressed in hepatocellular carcinoma. High level of SIRT1 correlates with higher tumor grade and stage and predicts poor long-term survival. The elevated SIRT1 protein is not attributable to elevation of mRNA level. The half-life of SIRT1 protein is longer in cell lines with high expression of SIRT1. We further demonstrate that SIRT1 is degraded by the 26S proteasome in an ubiquitin-dependent manner. Overexpression of SIRT1 promotes tumorigenesis and resists chemotherapeutical agent. In addition, we find some candidate proteins to be novel targets of SIRT1, including retinal dehydrogenase 1, nucleophosmin, heat shock cognate 71, heat shock protein 60, stress-70, heterogeneous nuclear ribonucleoprotein K, and heterogeneous nuclear ribonucleoprotein H. We find inhibition of SIRT1 might reduce ALDH1 enzymatic activity. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/38584 |
全文授權: | 有償授權 |
顯示於系所單位: | 病理學科所 |
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