Genetic alteration of Keap1 confers constitutive Nrf2 activation and resistance to chemotherapy in gallbladder cancer
Genetic alteration of Keap1 confers constitutive Nrf2 activation and resistance to chemotherapy in gallbladder cancer
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DOI：
10.1053/j.gastro.2008.06.082
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发表时间：
2008-10-01
期刊：
影响因子：
29.4
通讯作者：
Hirohashi, Setsuo
中科院分区：
文献类型：
--
作者：
Shibata, Tatsuhiro;Kokubu, Akiko;Hirohashi, Setsuo
背景和目标：胆道癌是一种高度恶性的肿瘤，迫切需要找到有效的治疗靶点以改善预后。存活基因的致癌激活对于癌细胞克服由其微环境（包括慢性炎症或暴露于抗癌药物）诱导的氧化应激是重要的。我们试图研究是否失调的Nrf 2，一个主转录因子的各种细胞保护基因对氧化应激，在BTC的致癌作用。研究方法：我们在BTC中筛选了Keap 1的遗传改变，Keap 1是Nrf 2的负调节因子，包括来自胆囊和肝外和肝内胆管的肿瘤。研究了癌症相关突变体Keap 1在Nrf 2抑制中的功能分析以及Nrf 2激活与5-氟尿嘧啶（5-FU）耐药之间的关系。结果如下：在BTC中观察到复发性（1/11细胞系和6/53原发性肿瘤）Keap 1基因改变，并且在胆囊癌（GBC）中尤其常见（4/13，30.7%）。这些改变导致Nrf 2抑制活性的相当大的损失，引起Nrf 2的组成性激活，并促进细胞增殖。通过Keap 1互补或Nrf 2短干扰RNA下调Nrf 2活性增加了Keap 1改变的BTC细胞对5-FU的敏感性。结论：Keap 1基因突变在胆囊癌中存在。由Keap 1改变引起的异常Nrf 2激活是GBC化疗耐药的分子机制之一，并将成为一种新的治疗靶点，作为对5-FU方案敏感性的增强剂。
Background & Aims: Biliary tract cancer (BTC) is a highly malignant tumor, and identification of effective therapeutic targets to improve prognosis is urgently required. Oncogenic activation of survival genes is important for cancer cells to overcome oxidative stresses induced by their microenvironments that include chronic inflammation or exposure to anticancer drugs. We attempted to examine whether deregulation of Nrf2, a master transcriptional factor of various cytoprotective genes against oxidative stress, plays a role in the carcinogenesis of BTC. Methods: We screened genetic alteration of Keap1, a negative regulator of Nrf2, in BTC including tumors originated from gallbladder and extra- and intrahepatic bile ducts. Functional analysis of cancer-related mutant Keap1 in Nrf2 repression and the association between Nrf2 activation and resistance to 5-fluorouracil (5-FU) were investigated. Results: Recurrent (in 1/11 cell lines and 6/53 primary tumors) Keap1 gene alterations were observed in BTC and were especially frequent (4/13, 30.7%) in gallbladder cancer (GBC). These alterations led to a considerable loss of Nrf2 repression activity, caused constitutive activation of Nrf2, and promoted cell proliferation. Down-regulation of Nrf2 activity by either Keap1 complementation or Nrf2 short interference RNA increased sensitivity to 5-FU in Keap1-altered BTC cells. Conclusions: Keap1 mutation occurs frequently in GBC. Aberrant Nrf2 activation provoked by Keap1 alteration is one of the molecular mechanisms for chemotherapeutic resistance in GBC and will be a novel therapeutic target as an enhancer of sensitivity to 5-FU-based regimens.