Nrf2：調控乳癌進程的關鍵因子

Nrf2：a key mediator in breast cancer progression

徐至蹼(Jhih-Pu Syu)

指導教授 ： 龔秀妮

國立臺灣大學/醫學院/解剖學暨細胞生物學研究所/博士(2016年)

https://doi.org/10.6342/NTU201702187

摘要

癌症是現代醫學難以治療的疾病之一，在臨床上尋找可預測的生物指標與治療標的是迫切需要的策略。近年來發現許多癌症相關的標的分子，其中轉錄相關因子nuclear factor erythroid 2-related factor 2(NFE2L2，Nrf2)有潛力成為腫瘤的治療標的。Nrf2是調控抗氧化酵素和解毒蛋白的重要轉錄因子，雖然正常細胞中Nrf2的活化可以賦予細胞更多的抗氧化及適應環境的能力，但在腫瘤細胞中，Nrf2的活化卻會使癌症更加惡化，許多研究認為Nrf2可以被視作致癌基因，可能影響癌症的發展。而在各種癌症中，乳癌在台灣盛行率年年升高，且是各大癌症中存活年數降低最多的，因而成為本論文的研究目標。在論文中，我們研究Nrf2對於乳癌惡化的影響，包括第一章的乳癌資料庫與microarray分析、第二章說明Nrf2與低氧誘導抗藥性的關係、第三章探討Nrf2藉由何種模式調控能量的產生、第四章討論Nrf2能否增加癌細胞在營養缺乏環境中的抵抗能力。在第一章的研究中，我們透過資料庫分析印證了Nrf2的表現量與乳癌病患存活率的關係。在第二章的研究中，我們證實了在低氧環境中，Nrf2的活化會透過ROS-Nrf2-GCLC-GSH訊息路徑誘導抗藥性的產生。在第三章的研究中，我們發現Nrf2可調控Sirt1/ Sirt3訊息途徑進而影響ATP生成，使癌細胞更加的惡化。在第四章的研究中，我們初步證實Nrf2在glutamine缺乏環境下可能調控ATF4訊息傳遞路徑，進而影響癌細胞對壓力的適應能力。綜上所述，Nrf2的活化會造成癌細胞的惡化，減少病患的存活率，透過抑制Nrf2的活性是一個抑制癌細胞惡化的方法，希望未來在乳癌的臨床治療上能提供另一個選擇。

關鍵字

Nuclear factor erythroid 2-related factor 2 (NFE2L2，Nrf2) ； 低氧誘導抗藥性 ； Sirt家族 ； 氧化壓力/Nrf2/GCLC/GSH訊息路徑 ； ATP產生 ； glutamine缺乏 ； ATF4

並列摘要

Cancer is one of the most difficult disease to cure in current medical terminology. With the development of targeted cancer therapies, predictable biomarkers play an increasingly key role in the clinical treatment. Nuclear factor erythroid-derived 2-like 2 (NFE2L2, Nrf2) is a transcription factor that directly mediates cellular stress signals. Traditionally, Nrf2 is regarded as a double-edged sword. The good effects on balance of oxidative stress are through the activation of Nrf2-related antioxidant downstream genes. The bad effects on chemotherapeutic resistance in cancer cells are also due to the activation of Nrf2-related stress adaptive downstream genes. Recently, many studies have implied that Nrf2 may be an oncogene, and it may provide cancer cells the advantages of cell growth, environment adaption and metastasis leading to cancer progression. Among various types of cancers, breast cancer has been selected due to thehigh incidence rates in Taiwan. In the thesis, we studied the relationship between Nrf2 and breast cancer progression, including chapter I: Array analysis of Nrf2 in breast cancer, chapter II: the relationship between Nrf2 and chemotherapy resistance under hypoxia, chapter III: How does Nrf2 upregulate cellular ATP production, and chapter IV: How does Nrf2 adapt to nutrient deprivation. In chapter I, the Nrf2 expression was associated with survival rate of breast cancer patients. In chapter II, Nrf2 served as a key regulator in chemotherapeutic resistance under hypoxia through ROS-Nrf2-GCLC-GSH pathway. In chapter III, Nrf2 promoted cancer progression by increasing ATP production through Sirt1/ Sirt3 signaling pathways. In chapter IV, our preliminary data showed that the ability of cellular adaptation ability was increased through ATF4 signaling pathway in Nrf2 overexpressed breast cancer cells under glutamine deficiency. Taken together, targeting Nrf2 can be a potential treatment in breast cancer therapy, and could be another therapeutic choice in clinic in the future.

並列關鍵字

Nuclear factor erythroid-derived 2-like 2 (NFE2L2, Nrf2) ； hypoxia-induced drug resistance ； SIRT family ； ROS-Nrf2-GCLC-GSH pathway ； ATP production ； ATF4 ； glutamine deficiency

參考文獻

166. Hagen T. Oxygen versus Reactive Oxygen in the Regulation of HIF-1alpha: The Balance Tips. Biochem Res Int. 2012; 2012:436981.

1. Syu JP, Chi JT and Kung HN. Nrf2 is the key to chemotherapy resistance in MCF7 breast cancer cells under hypoxia. Oncotarget. 2016; 7(12):14659-14672.

2. Zhang M, Zhang C, Zhang L, Yang Q, Zhou S, Wen Q and Wang J. Nrf2 is a potential prognostic marker and promotes proliferation and invasion in human hepatocellular carcinoma. BMC Cancer. 2015; 15:531.

3. Chapple SJ, Siow RC and Mann GE. Crosstalk between Nrf2 and the proteasome: therapeutic potential of Nrf2 inducers in vascular disease and aging. Int J Biochem Cell Biol. 2012; 44(8):1315-1320.

4. Canning P, Sorrell FJ and Bullock AN. Structural basis of Keap1 interactions with Nrf2. Free Radic Biol Med. 2015; 88(Pt B):101-107.