NRF2 Intensifies Host Defense Systems to Prevent Lung Carcinogenesis, but After Tumor Initiation Accelerates Malignant Cell Growth
NRF2 Intensifies Host Defense Systems to Prevent Lung Carcinogenesis, but After Tumor Initiation Accelerates Malignant Cell Growth
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DOI：
10.1158/0008-5472.can-15-1584
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发表时间：
2016-05-15
期刊：
影响因子：
11.2
通讯作者：
Yamamoto, Masayuki
中科院分区：
文献类型：
--
作者：
Satoh, Hironori;Moriguchi, Takashi;Yamamoto, Masayuki
在动物模型中，Nrf 2激活促进对化学致癌作用的抵抗，但Nrf 2的激活突变也通过激活抗氧化/解毒酶和代谢重编程赋予人类细胞恶性特征。在这项研究中，我们研究了这些矛盾的活动Nrf 2，癌症化学预防和癌细胞生长的增强，可以调和在一个建立的小鼠模型，肺癌诱导的肺癌。使用Keap 1敲除（kd）小鼠，表达高水平的Nrf 2，我们发现尿烷被迅速排泄到尿液中，与尿烷解毒基因表达的上调一致。因此，与野生型小鼠相比，Keap 1-kd小鼠中的肿瘤明显更小，频率更低。相反，来自Keap 1-kd小鼠并移植到裸鼠中的肿瘤细胞与来自野生型小鼠的细胞相比表现出更高的致瘤性。为了确定移植模型中肿瘤生长表型的因素，我们进行了微阵列分析，发现许多抗氧化应激基因在Keap 1-kd衍生的肿瘤中上调。因此，我们认为癌细胞中的Nrf 2激活增强了它们的致瘤性，但在Keap 1-kd小鼠中，全局Nrf 2激活同时增强了抗癌免疫力，从而抑制了Keap 1-kd肿瘤的生长潜力。我们的研究结果提供了相关的洞察Nrf 2在癌症中的双重作用，并保证Nrf 2在不同阶段的致癌功能的进一步研究。(C)2016年AACR。
Nrf2 activation promotes resistance to chemical carcinogenesis in animal models, but activating mutations in Nrf2 also confer malignant characters to human cells by activating antioxidative/detoxifying enzymes and metabolic reprogramming. In this study, we examined how these contradictory activities of Nrf2, cancer chemoprevention and cancer cell growth enhancement, can be reconciled in an established mouse model of urethane-induced lung carcinogenesis. Using Keap1-knockdown (kd) mice, which express high levels of Nrf2, we found that urethane was rapidly excreted into the urine, consistent with an upregulation in the expression of urethane detoxification genes. Consequently, urethane-induced tumors were significantly smaller and less frequent in Keap1-kd mice than in wild-type mice. In contrast, tumor cells derived from Keap1-kd mice and transplanted into nude mice exhibited higher tumorigenicity compared with cells derived from wild-type mice. To identify the factors contributing to the tumor growth phenotype in the transplantation model, we performed a microarray analysis and found that many antioxidative stress genes were upregulated in the Keap1-kd-derived tumors. Therefore, we suggest that Nrf2 activation in cancer cells enhances their tumorigenicity, but global Nrf2 activation, as in Keap1-kd mice, simultaneously enhances anticancer immunity, thereby suppressing the growth potential of Keap1-kd tumors. Our findings provide relevant insight into the dual role of Nrf2 in cancer and warrant further studies of Nrf2 function during different stages of carcinogenesis. (C) 2016 AACR.