2015-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/659192摘要：Nrf2是一個調節細胞受氧化壓力反應的轉錄因子，它平時受Keapl調節其表現 維持在低量，當細胞受到氧化壓力時，Keapl去活化，使Nrf2表現量增加，因 而推動下游基因的轉錄。在某些癌症，包括肝細胞癌和皮膚癌，Nrf2或Keapl 基因的突變造成Nrf2的過度活化，但為何Nrf2過度活化會促進癌症的生成， 其機制仍未明。我們的初步研究發現，Nrf2在肝細胞癌經常過度表現而且減少 Nrf2的量會影響肝細胞癌的生長。在本研究中，我們將探討Nrf2在癌症發生 的角色，並且找出其致癌的關鍵下游蛋白。此外，我們將建立一個表現過度活 化Nrf2的轉殖小鼠，以更直接的方式證明Nrf2可促進細胞生長和癌化。我們 的目標包括：(一）決定Nrf2在肝細胞癌的表現頻率及其表現的臨床病理意義。(二）次定Nrf2在腫瘤生成和侵犯的角色。(三）找出Nrf2致癌的關鍵下游蛋白。(四）建立表現過度活化Nrf2的轉殖小鼠，證明Nrf2可促進細胞生長和癌 化。<br> Abstract: Nrf2 is a transcription factor that regulates cellular response to oxidative stress. In normal status, it is regulated by Keap1 to maintain a low level expression. When cells suffer from oxidative stress, Keap1 is inactivated and Nrf2 is stabilized to turn on the transcription of downstream targets. In certain types of cancer, including hepatocellular carcinoma (HCC) and skin cancer, mutations in Nrf2 or Keap1 genes cause overactivity of Nrf2. However, why overactivity of Nrf2 induces tumor formation is still unknown. Our preliminary results show that Nrf2 is frequently overexpressed in HCC and knockdown of Nrf2 in HCC cell line affects tumor growth. In this proposal, we will study the roles of Nrf2 in the carcinogenesis of HCC and try to find the key downstream targets of oncogenic process. Besides, we will generate a transgenic mice model with overactive Nrf2 to further prove the role of Nrf2 in cell proliferation and tumorigenesis. Our aims include:Aim 1. To determine the expression frequency of Nrf2 in HCC and the clinicopathologic significance of Nrf2 expression in HCC.Aim 2. To determine the roles of Nrf2 in the tumor formation and invasion of HCC.Aim 3. To identify the oncogenes activated by Nrf2 and study the mechanism of their regulation.Aim 4. To generate a transgenic mice model with overactive Nrf2 to prove the role of Nrf2 in cell proliferation and tumorigenesis.Nrf2致癌基因肝細胞癌轉殖小鼠Nrf2oncogenehepatocellular carcinomatransgenic mice