修回日期: 2014-05-09
接受日期: 2014-05-14
在线出版日期: 2014-07-18
核因子E2相关因子2(nuclear factor E2-related factor 2, Nrf2)对机体抗氧化应激有重要作用, 他既可以预防正常细胞恶变, 也可以促进肿瘤的发展, 同时也能增加肿瘤细胞对化疗药物的耐受性. 胃癌是消化系最常见的恶性肿瘤之一, 而且在治疗方面存在着耐药性, 其病死率仍高居不下, 严重威胁着人类健康. 肿瘤的化学预防是目前肿瘤治疗的热点. Keleh样环氧氯丙烷相关蛋白1(Keleh-like ECH-associated protein 1, Keap1)-Nrf2-抗氧化反应元件信号通路不仅与胃癌的发生有关, 同时也被视为胃癌化学预防的分子靶标. 本文就该信号通路的组成及其与胃癌化学预防关系的研究进展作一综述, 为胃癌的预防和治疗提供新思路.
核心提示: 本文不仅综述了核因子E2相关因子2(nuclear factor E2-related factor 2, Nrf2)-抗氧化反应元件(antioxidant response element, ARE)通路, 还阐述了他在胃癌的发生发展的促进作用, 以及多种天然化合物通过作用于Nrf2-ARE通路在胃癌在化学预防机制. 若以该通路为靶点, 研发新型高效的化学预防制剂, 将会为胃癌的防治开辟一片新天地.
引文著录: 蒋龙超, 唐世孝. Keap1-Nrf2-ARE信号通路及其与胃癌化学预防的研究进展. 世界华人消化杂志 2014; 22(20): 2845-2850
Revised: May 9, 2014
Accepted: May 14, 2014
Published online: July 18, 2014
Nuclear factor E2-related factor 2 (Nrf2) plays an important role in the body's anti-oxidative stress system. Although Nrf2 can prevent the malignant transformation of normal cells, it also can promote tumor development and increase the resistance of tumor cells to chemotherapeutic drugs. Gastric cancer is one of the most common malignant tumors of the digestive system with high mortality, posing a serious threat to human health. Since chemotherapy resistance is common in cancer treatment, cancer chemoprevention has become a hot spot of tumor treatment. The Keap1-Nrf2-ARE signaling pathway is related to the occurrence of gastric cancer, representing a molecular target for gastric cancer chemoprevention. This paper summarizes the recent progress in understanding the relationship between the Keap1-Nrf2-ARE signaling pathway and gastric cancer chemoprevention.
- Citation: Jiang LC, Tang SX. Keap1-Nrf2-ARE signaling pathway and gastric cancer chemoprevention. Shijie Huaren Xiaohua Zazhi 2014; 22(20): 2845-2850
- URL: https://www.wjgnet.com/1009-3079/full/v22/i20/2845.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v22.i20.2845
最新统计显示, 胃癌在我国乃至全球癌症新发病率及病死率方面仍高居不下[1]. 胃癌的发病机制非常复杂, 他的发生发展是个多因素、多阶段的分子生物学过程, 细胞氧化还原稳态的改变与胃癌的发生发展有密切联系. 正常细胞的生长依赖于自身的氧化还原稳态, 核因子E2相关因子2(nuclear factor E2-related factor 2, Nrf2)是维持这种稳态的关键因子, 且Nrf2对全身多个器官或组织具有保护作用[2,3]. Nrf2能增强细胞应对氧化应激的能力, 而Keleh样环氧氯丙烷相关蛋白1(Keleh-like ECH-associated protein 1, Keap1)是Nrf2的一个重要负性调节因子, 通过与抗氧化反应元件(antioxidant response element, ARE)相互作用, 调节抗氧化蛋白和Ⅱ相解毒酶的表达[4,5]. 多项研究[6-9]证实Keap1-Nrf2-ARE信号通路既可以预防正常细胞癌变, 也可以促进肿瘤的发展, 同时也是癌症化学预防的一个潜在靶点.
Moi等[10]于1994年最先发现Nrf2能够与β-珠蛋白基因启动子的NF-E2/AP1基因片段结合, 后将其克隆而逐步研究其特征. 最初发现Nrf2在诸如肝脏、心血管、神经系统、肺和消化系等多种组织细胞中表达, 但认为对细胞的作用不大[3,11]. 直到后来研究者在Nrf2基因敲除小鼠相关实验中发现抗氧化活性及相关基因表达下降, 对此才有了更深入的研究[12]. Nrf2是一种转录相关蛋白, 其含有6个高度保守的结构域Neh, 分别为Nehl-Neh6. Nehl区含有能够识别结合ARE并启动转录的亮氨酸拉链结构bZip[13]. Neh2区是Nrf2与蛋白Keap1结合区, 含多个赖氨酸残基, 以泛素化方式使Nrf2降解而具有负性调控活性[14]. Neh3区对Nrf2下游多种抗氧化反应元件依赖性基因的转录激活具有重要作用[15]. Neh4及Neh5是参与启动下游基因转录的结构域, Nrf2-Maf与ARE结合, 并且需要相关辅助蛋白和Neh4、Neh5结合进而启动转录过程[16,17]. 目前, Neh6区的功能尚不清楚, 仅发现其富含丝氨酸残基[18]. Keap1是一个伴侣蛋白, 含有5个结构域, 即双甘氨酸重复区DGR、C端结构域(C-terminal region, CTR)、BTB区(broad complex, tramtrack and Bric-à-Brac)、干预区(intervening region, IVR)和N端结构域(N-terminal region, NTR)[19,20]. Keap1在正常状态下处于"关闭"状态, 使Nrf2泛素化而被降解, 从而减少胞质中的Nrf2向核内转移; 在受到应激时处于"开放"状态, 使Nrf2进入核内, 与ARE结合启动转录; 当恢复平衡后又回到"关闭"状态, 使细胞核内、外的Nrf2恢复到原来的水平, 如此周而复始的循环, 维持细胞的氧化还原稳态[21,22]. ARE最先由Rushmore等[23]和Friling等[24]在研究Ya基因时发现的. 直到Nrf2被发现后才逐渐认识到ARE是一个抗氧化调控元件, 也是一个特异的DNA启动子结合序列, 位于Ⅱ相代谢酶基因的调控区[25]. 研究[26-28]发现: 在ARE发挥其调节作用的过程中, 有两种蛋白质参与了相关信号的传递, 即Nrf2和Keap1; 当活化的Nrf2与Keap1分离后进入核内与ARE结合,从而调节下游产物的表达, 包括谷胱甘肽S转移酶(glutathione S-transferase, GSTs)、NAD(P)H: 醌氧化还原酶1[NAD(P)H: quinone oxidoreductase 1, NQ01]、血红素加氧酶1(hemeoxygenase-1, HO-1)等, 产生的各种蛋白酶类参与有害物质的代谢, 对细胞起到保护作用.
活性氧(reactive oxygen species, ROS)是机体在氧化应激下产生的, 可损伤胞内各种大分子物质, 是大多数疾病发生的病理生理基础. 而机体内存在极其复杂的氧化应激应答系统, 自身可以产生一系列保护性蛋白, 使细胞免受外界损害[29,30]. Pickering等[31]通过应用过氧化氢处理秀丽隐杆线虫等实验发现: 细胞死亡与氧化蛋白的积累有关; 而蛋白酶可以分解氧化的蛋白, 在氧化应激过程中, Nrf2能够加速蛋白酶的产生, 因此Nrf2可以增强细胞应付氧化应激的能力. 正常细胞内存在一种原癌基因与抑癌基因的平衡, 而肿瘤本身是一种基因病, 当细胞内部的这种平衡发生改变后, 使基因发生突变及一系列复杂的变化, 最终导致肿瘤的发生. 细胞原癌基因与抑癌基因之间平衡的改变主要和遗传, 物理、化学、生物因素刺激及一些癌前病变有关, 这些因素都会使细胞的氧化还原稳态发生改变, 因而肿瘤的发生与氧化应激密切相关. Nrf2在致癌的环境下可以保护正常细胞, 但是在化疗药物以及过氧环境下可以保护肿瘤细胞.
科学家们通过大量实验发现Nrf2与肝癌[8]、口腔癌[32]、结肠肿瘤[33]、乳腺癌[34]、胰腺癌[35]、肺癌[36]、食管癌[37]等病变的发生发展有密切联系. 当使用过氧化氢(过氧化氢是化疗过程中主要产物)处理肿瘤细胞时发现肿瘤细胞Nrf2会加速蛋白酶的产生, 另外当使用抑制剂阻断Nrf2时, 肿瘤细胞生成蛋白酶以及处理双氧水的能力减弱, 表明Nrf2可通过增强肿瘤细胞对化疗药物的耐受性而促进肿瘤细胞增殖[31]. 诸如此类的研究均表明肿瘤细胞中ROS增多, 活化的Nrf2进入细胞核, 通过Keap1-Nrf2-ARE通路信号转导, 参与清除ROS, 从而对肿瘤细胞起到保护作用, 促进肿瘤发生发展, 同时也是肿瘤耐药产生的原因.
和其他肿瘤一样, 胃癌的发生发展与氧化还原稳态失衡有关. 众所周知胃癌及其癌前病变都与幽门螺杆菌、环氧合酶-2(cyclooxygenase-2, COX-2)、诱导型一氧化氮合酶(inducible nitric oxide synthase, iNOS)以及某些病毒感染相关, 他们从不同的途径改变胃黏膜细胞的氧化还原稳态, 产生大量的ROS, 促进胃癌的发生. 有文献报道[38]促炎症因子[如白介素-1b(interleukin-1b, IL-1b)、IL-8、IL-11、肿瘤坏死因子-α(tumor necrosis factor α, TNF-α)及干扰素-g(interferon-g, IFN-g)]可使胃癌前病变产生氧化应激, 然后通过某些信号转导通路促进癌前病变的进程. Wang等[39]研究发现在正常胃黏膜、胃癌前病变及胃癌中, Nrf2的表达逐渐升高, 且差异有统计学意义. Nrf2在核内堆积的主要原因是Nrf2或Keap1突变引起的[40]. Singh等[41]通过同位素示踪发现NRF2调节的miR-1和miR-206的可以使糖代谢发生改变, 促进肿瘤的发生发展.
目前, 肿瘤耐药性成为在肿瘤治疗方面的一个瓶颈, 多数肿瘤对化疗药物的耐受性增加, 导致治疗效果不理想. 其中Keap1-Nrf2-ARE信号通路已被证明是导致肿瘤耐药的原因之一, 主要与调节下游基因表达(如GSTs、NQ01、HO-1等)、激活热休克蛋白、上调Bcl-2等机制有关[42-44]. 癌症化学预防(cancer chemoprevention)是Sporn在1976年提出来的, 是指利用天然、合成或生物物质来阻止、减缓或者逆转癌症发生发展过程, 从而降低癌症发生率和死亡率的方法策略[45]. 他的提出为肿瘤的治疗提供了新思路. 一般来说, 肿瘤的发生发展涉及3个阶段: 初始、推进和进展阶段, 初始阶段是DNA发生不可逆损伤的阶段, 而推进和进展阶段是可逆的[46]. 科学家们通过各种动物模型[47,48]发现肿瘤的3个阶段均可以使用化学物质进行干预, 而且在多年的流行病学调查中发现化学预防同样可以降低高危人群肿瘤的发生率.
化学致癌物从细胞和机体中清除过程可分为Ⅰ期和Ⅱ期. 首先经Ⅰ相代谢酶作用后, 在疏水的化学致癌物中引入羟基; 接着在肝脏Ⅱ相代谢酶作用下, 在已产生的羟基上再糖基化, 进一步提高化合物的水溶性而促进其排出体外. 与Ⅰ相酶不同的是, Ⅱ相代谢酶的诱导不会增加致癌风险, 可通过诱导Ⅱ相代谢酶的活性进行化学防癌. 我们知道Nrf2可通过与抗氧化反应元件ARE相互作用, 调节抗氧化蛋白和Ⅱ相解毒酶的表达, 因此Nrf2信号通路是化学防癌的重要研究方向. 已发现有多种天然化合物经Nrf2/ARE通路诱导Ⅱ相代谢酶表达而发挥化学防癌作用.
莱菔硫烷是异硫氰酸盐的一种, 可以上调ARE介导的酶活性[49]. 他可以通过与Keap1结构中巯基作用, 直接影响Keap1与结合Nrf2, 促进Nrf2活化转入细胞核, 激活NQO1、GST等Ⅱ相代谢酶, 而在Nrf2基因缺失的小鼠实验对比发现, 其上调Ⅱ相代谢酶的作用不明显. 莱菔硫烷通过激活Nrf2通路对抗致癌物质诱导的肿瘤发生, 起到细胞保护的作用[50]. 姜黄素是从植物茎中提取的酚类色素, 大量实验已经证明其可以抑制肿瘤的起始阶段和促进阶段. Jones等[51]通过喂养大鼠姜黄素, 发现大鼠组织内的GST活性显著提高, NQO1的活性也有所增加, 证明姜黄素可以提高Ⅱ相解毒酶的活性, 具有化学预防作用. Garg等[52]通过在小鼠饲料中添加姜黄素喂养, 发现给药组小鼠的组织GST、NQO1的活性、蛋白和mRNA的表达与对照组有着显著性差异, 且差异具有统计学意义. 姜黄素能以剂量和时间依赖方式促进细胞中Nrf2的表达, 同时伴随HO-1蛋白表达以及活性的增加. 研究[53]表明, 姜黄素通过使Nrf2-Keap1复合体解离, 促使Nrf2与ARE结合从而增加HO-1基因表达. 白藜芦醇是从植物的根茎中提取的, 具有抗氧化活性. 用不同浓度的白藜芦醇处理人肺腺癌细胞, 发现加入白藜芦醇的细胞GSH的活性和蛋白水平都有显著性提高, ROS的量相对于对照组显著降低, 利用荧光素酶发现细胞核内Nrf2水平大量增加, 而敲除Nrf2基因后再加入白藜芦醇, 发现这些氧化还原酶的量并没有提高, 提示白藜芦醇是通过Nrf2途径增加抗氧化酶的表达[54]. 还有研究[55]发现类胡萝卜素中番茄红素也具有抗氧化活性, 他可以通过激活Nrf2入核, 从而激活下游氧化还原酶HO-1等的表达, 保护细胞免受氧化伤害. 这些天然化合物可以通过诱导Ⅱ相代谢酶及抗氧化酶的表达, 促进致癌物的生物转化, 阻断或抑制胃癌的发展进程, 由此我们相信通过研发Nrf2及其上、下游基因相关的抑制剂或激动剂对于胃癌的化学预防有至关重要的作用.
Keap1-Nrf2-ARE信号通路是近年来的研究热点, 他不仅可以保护正常细胞恶变, 还可以促进肿瘤的发生发展, 同时还与肿瘤的耐药相关. 与其他肿瘤一样, 胃癌细胞中存在着Nrf2的异常表达, 我们可以通过以Keap1-Nrf2-ARE轴为靶点, 研究出新型高效的化学预防制剂, 为胃癌的防治开辟一片新天地.
胃癌是消化系最常见的恶性肿瘤之一, 而且在治疗方面存在着耐药性, 其病死率仍高居不下, 严重威胁着人类健康. 肿瘤的化学预防是目前肿瘤治疗热点.
李正荣, 副教授, 副主任医师, 南昌大学附属第一医院胃肠外科(普六病区)
胃癌耐药性是目前治疗一个难题, 研究发现核因子E2相关因子2( nuclear factor E2-related factor 2, Nrf2)与肿瘤耐药性密切相关, 针对此研究新型高效的化学预防制剂成为胃癌治疗一个重点和难点.
大量实验发现Nrf2与肝癌、结肠肿瘤、胰腺癌、食管癌等病变的有密切联系. Wang等发现在胃癌Nrf2的过度表达. Nrf2在核内堆积的主要原因是Nrf2或Keap1突变引起. 研究发现多种天然化合物可通过可以通过诱导Ⅱ相代谢酶及抗氧化酶的表达, 干预胃癌的发展进程.
目前单纯研究"Keap1-Nrf2-ARE信号通路"和"胃癌化学预防"的文献较多, 本文不仅介绍了该通路, 还重点介绍了他与胃癌的关系, 以及多种天然化合物在胃癌在化学预防机制中与该通路关系.
本文综述了多种天然化合物通过作用于Nrf2-ARE通路在胃癌在化学预防机制. 以Keap1-Nrf2-ARE轴为靶点, 研发新型高效的化学预防制剂, 将会为胃癌的防治开辟一片新天地.
本文以Nrf2-ARE信号通路与胃癌防治的联系为出发点, 对胃癌的治疗具有重要意义.
编辑 郭鹏 电编 鲁亚静
| 1. | Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69-90. [PubMed] [DOI] |
| 3. | Lee JM, Li J, Johnson DA, Stein TD, Kraft AD, Calkins MJ, Jakel RJ, Johnson JA. Nrf2, a multi-organ protector? FASEB J. 2005;19:1061-1066. [PubMed] [DOI] |
| 4. | Nguyen T, Sherratt PJ, Pickett CB. Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annu Rev Pharmacol Toxicol. 2003;43:233-260. [PubMed] [DOI] |
| 5. | Sykiotis GP, Bohmann D. Keap1/Nrf2 signaling regulates oxidative stress tolerance and lifespan in Drosophila. Dev Cell. 2008;14:76-85. [PubMed] [DOI] |
| 6. | Solis LM, Behrens C, Dong W, Suraokar M, Ozburn NC, Moran CA, Corvalan AH, Biswal S, Swisher SG, Bekele BN. Nrf2 and Keap1 abnormalities in non-small cell lung carcinoma and association with clinicopathologic features. Clin Cancer Res. 2010;16:3743-3753. [PubMed] [DOI] |
| 7. | Lister A, Nedjadi T, Kitteringham NR, Campbell F, Costello E, Lloyd B, Copple IM, Williams S, Owen A, Neoptolemos JP. Nrf2 is overexpressed in pancreatic cancer: implications for cell proliferation and therapy. Mol Cancer. 2011;10:37. [PubMed] [DOI] |
| 8. | Nishimura J, Dewa Y, Okamura T, Jin M, Saegusa Y, Kawai M, Umemura T, Shibutani M, Mitsumori K. Role of Nrf2 and oxidative stress on fenofibrate-induced hepatocarcinogenesis in rats. Toxicol Sci. 2008;106:339-349. [PubMed] [DOI] |
| 9. | Bishayee A, Barnes KF, Bhatia D, Darvesh AS, Carroll RT. Resveratrol suppresses oxidative stress and inflammatory response in diethylnitrosamine-initiated rat hepatocarcinogenesis. Cancer Prev Res (Phila). 2010;3:753-763. [PubMed] [DOI] |
| 10. | Moi P, Chan K, Asunis I, Cao A, Kan YW. Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc Natl Acad Sci U S A. 1994;91:9926-9930. [PubMed] |
| 11. | Satoh T, Okamoto SI, Cui J, Watanabe Y, Furuta K, Suzuki M, Tohyama K, Lipton SA. Activation of the Keap1/Nrf2 pathway for neuroprotection by electrophilic [correction of electrophillic] phase II inducers. Proc Natl Acad Sci U S A. 2006;103:768-773. [PubMed] [DOI] |
| 12. | Chan K, Lu R, Chang JC, Kan YW. NRF2, a member of the NFE2 family of transcription factors, is not essential for murine erythropoiesis, growth, and development. Proc Natl Acad Sci U S A. 1996;93:13943-13948. [PubMed] |
| 13. | Jain AK, Bloom DA, Jaiswal AK. Nuclear import and export signals in control of Nrf2. J Biol Chem. 2005;280:29158-29168. [PubMed] [DOI] |
| 14. | Zhang DD, Lo SC, Cross JV, Templeton DJ, Hannink M. Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Mol Cell Biol. 2004;24:10941-10953. [PubMed] [DOI] |
| 15. | Nioi P, Nguyen T, Sherratt PJ, Pickett CB. The carboxy-terminal Neh3 domain of Nrf2 is required for transcriptional activation. Mol Cell Biol. 2005;25:10895-10906. [PubMed] [DOI] |
| 16. | Katoh Y, Itoh K, Yoshida E, Miyagishi M, Fukamizu A, Yamamoto M. Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription. Genes Cells. 2001;6:857-868. [PubMed] [DOI] |
| 17. | Zhang DD. Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metab Rev. 2006;38:769-789. [PubMed] [DOI] |
| 18. | Giudice A, Arra C, Turco MC. Review of molecular mechanisms involved in the activation of the Nrf2-ARE signaling pathway by chemopreventive agents. Methods Mol Biol. 2010;647:37-74. [PubMed] [DOI] |
| 19. | Kwak MK, Wakabayashi N, Kensler TW. Chemoprevention through the Keap1-Nrf2 signaling pathway by phase 2 enzyme inducers. Mutat Res. 2004;555:133-148. [PubMed] [DOI] |
| 20. | Lau A, Villeneuve NF, Sun Z, Wong PK, Zhang DD. Dual roles of Nrf2 in cancer. Pharmacol Res. 2008;58:262-270. [PubMed] [DOI] |
| 21. | Kang MI, Kobayashi A, Wakabayashi N, Kim SG, Yamamoto M. Scaffolding of Keap1 to the actin cytoskeleton controls the function of Nrf2 as key regulator of cytoprotective phase 2 genes. Proc Natl Acad Sci U S A. 2004;101:2046-2051. [PubMed] [DOI] |
| 22. | Baird L, Dinkova-Kostova AT. The cytoprotective role of the Keap1-Nrf2 pathway. Arch Toxicol. 2011;85:241-272. [PubMed] [DOI] |
| 23. | Rushmore TH, Pickett CB. Transcriptional regulation of the rat glutathione S-transferase Ya subunit gene. Characterization of a xenobiotic-responsive element controlling inducible expression by phenolic antioxidants. J Biol Chem. 1990;265:14648-14653. [PubMed] |
| 24. | Friling RS, Bensimon A, Tichauer Y, Daniel V. Xenobiotic-inducible expression of murine glutathione S-transferase Ya subunit gene is controlled by an electrophile-responsive element. Proc Natl Acad Sci U S A. 1990;87:6258-6262. [PubMed] |
| 25. | Kensler TW, Wakabayashi N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol. 2007;47:89-116. [PubMed] [DOI] |
| 26. | Yates MS, Kensler TW. Chemopreventive promise of targeting the Nrf2 pathway. Drug News Perspect. 2007;20:109-117. [PubMed] |
| 27. | Tkachev VO, Menshchikova EB, Zenkov NK. Mechanism of the Nrf2/Keap1/ARE signaling system. Biochemistry (Mosc). 2011;76:407-422. [PubMed] |
| 28. | Kansanen E, Jyrkkänen HK, Levonen AL. Activation of stress signaling pathways by electrophilic oxidized and nitrated lipids. Free Radic Biol Med. 2012;52:973-982. [PubMed] [DOI] |
| 29. | Wang Y, Yang J, Yi J. Redox sensing by proteins: oxidative modifications on cysteines and the consequent events. Antioxid Redox Signal. 2012;16:649-657. [PubMed] [DOI] |
| 30. | Buelna-Chontal M, Zazueta C. Redox activation of Nrf2 & amp; NF-κB: a double end sword. Cell Signal. 2013;25:2548-2557. [PubMed] [DOI] |
| 31. | Pickering AM, Staab TA, Tower J, Sieburth D, Davies KJ. A conserved role for the 20S proteasome and Nrf2 transcription factor in oxidative stress adaptation in mammals, Caenorhabditis elegans and Drosophila melanogaster. J Exp Biol. 2013;216:543-553. [PubMed] [DOI] |
| 32. | Huang CF, Zhang L, Ma SR, Zhao ZL, Wang WM, He KF, Zhao YF, Zhang WF, Liu B, Sun ZJ. Clinical significance of Keap1 and Nrf2 in oral squamous cell carcinoma. PLoS One. 2013;8:e83479. [PubMed] [DOI] |
| 33. | Geillinger KE, Kipp AP, Schink K, Röder PV, Spanier B, Daniel H. Nrf2 regulates the expression of the peptide transporter PEPT1 in the human colon carcinoma cell line Caco-2. Biochim Biophys Acta. 2014;1840:1747-1754. [PubMed] [DOI] |
| 34. | Onodera Y, Motohashi H, Takagi K, Miki Y, Shibahara Y, Watanabe M, Ishida T, Hirakawa H, Sasano H, Yamamoto M. NRF2 immunolocalization in human breast cancer patients as a prognostic factor. Endocr Relat Cancer. 2014;21:241-252. [PubMed] [DOI] |
| 35. | Soini Y, Eskelinen M, Juvonen P, Kärjä V, Haapasaari KM, Saarela A, Karihtala P. Nuclear Nrf2 expression is related to a poor survival in pancreatic adenocarcinoma. Pathol Res Pract. 2014;210:35-39. [PubMed] [DOI] |
| 36. | Sasaki H, Suzuki A, Shitara M, Hikosaka Y, Okuda K, Moriyama S, Yano M, Fujii Y. Genotype analysis of the NRF2 gene mutation in lung cancer. Int J Mol Med. 2013;31:1135-1138. [PubMed] [DOI] |
| 37. | Mao JT, Tangsakar E, Shen H, Wang ZQ, Zhang MX, Chen JX, Zhang G, Wang JS. [Expression and clinical significance of Nrf2 in esophageal squamous cell carcinoma]. Xibao Yu Fenzi Mianyixue Zazhi. 2011;27:1231-1233. [PubMed] |
| 39. | Wang HB, Zhou CJ, Song SZ, Chen P, Xu WH, Liu B, Zhu KX, Yu WH, Wu HL, Wang HJ. Evaluation of Nrf2 and IGF-1 expression in benign, premalignant and malignant gastric lesions. Pathol Res Pract. 2011;207:169-173. [PubMed] [DOI] |
| 40. | Yoo NJ, Kim HR, Kim YR, An CH, Lee SH. Somatic mutations of the KEAP1 gene in common solid cancers. Histopathology. 2012;60:943-952. [PubMed] [DOI] |
| 41. | Singh A, Happel C, Manna SK, Acquaah-Mensah G, Carrerero J, Kumar S, Nasipuri P, Krausz KW, Wakabayashi N, Dewi R. Transcription factor NRF2 regulates miR-1 and miR-206 to drive tumorigenesis. J Clin Invest. 2013;123:2921-2934. [PubMed] [DOI] |
| 42. | Tanaka S, Akaike T, Fang J, Beppu T, Ogawa M, Tamura F, Miyamoto Y, Maeda H. Antiapoptotic effect of haem oxygenase-1 induced by nitric oxide in experimental solid tumour. Br J Cancer. 2003;88:902-909. [PubMed] [DOI] |
| 43. | Ahmed K, Furusawa Y, Tabuchi Y, Emam HF, Piao JL, Hassan MA, Yamamoto T, Kondo T, Kadowaki M. Chemical inducers of heat shock proteins derived from medicinal plants and cytoprotective genes response. Int J Hyperthermia. 2012;28:1-8. [PubMed] [DOI] |
| 44. | Niture SK, Jaiswal AK. Nrf2 protein up-regulates antiapoptotic protein Bcl-2 and prevents cellular apoptosis. J Biol Chem. 2012;287:9873-9886. [PubMed] [DOI] |
| 45. | Sporn MB, Dunlop NM, Newton DL, Smith JM. Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids). Fed Proc. 1976;35:1332-1338. [PubMed] |
| 46. | Hu R, Saw CL, Yu R, Kong AN. Regulation of NF-E2-related factor 2 signaling for cancer chemoprevention: antioxidant coupled with antiinflammatory. Antioxid Redox Signal. 2010;13:1679-1698. [PubMed] [DOI] |
| 47. | Bosland MC. Use of animal models in defining efficacy of chemoprevention agents against prostate cancer. Eur Urol. 1999;35:459-463. [PubMed] |
| 48. | Corpet DE, Pierre F. Point: From animal models to prevention of colon cancer. Systematic review of chemoprevention in min mice and choice of the model system. Cancer Epidemiol Biomarkers Prev. 2003;12:391-400. [PubMed] |
| 49. | Ye L, Zhang Y. Total intracellular accumulation levels of dietary isothiocyanates determine their activity in elevation of cellular glutathione and induction of Phase 2 detoxification enzymes. Carcinogenesis. 2001;22:1987-1992. [PubMed] [DOI] |
| 50. | Thimmulappa RK, Mai KH, Srisuma S, Kensler TW, Yamamoto M, Biswal S. Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res. 2002;62:5196-5203. [PubMed] |
| 51. | Jones SB, Brooks JD. Modest induction of phase 2 enzyme activity in the F-344 rat prostate. BMC Cancer. 2006;6:62. [PubMed] [DOI] |
| 52. | Garg R, Gupta S, Maru GB. Dietary curcumin modulates transcriptional regulators of phase I and phase II enzymes in benzo[a]pyrene-treated mice: mechanism of its anti-initiating action. Carcinogenesis. 2008;29:1022-1032. [PubMed] [DOI] |
| 53. | Balogun E, Hoque M, Gong P, Killeen E, Green CJ, Foresti R, Alam J, Motterlini R. Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element. Biochem J. 2003;371:887-895. [PubMed] [DOI] |
| 54. | Kode A, Rajendrasozhan S, Caito S, Yang SR, Megson IL, Rahman I. Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2008;294:L478-L488. [PubMed] |
| 55. | Lian F, Wang XD. Enzymatic metabolites of lycopene induce Nrf2-mediated expression of phase II detoxifying/antioxidant enzymes in human bronchial epithelial cells. Int J Cancer. 2008;123:1262-1268. [PubMed] [DOI] |