Nrf2 gene mutation and single nucleotide polymorphism rs6721961 of the Nrf2 promoter region in renal cell cancer
Nrf2 gene mutation and single nucleotide polymorphism rs6721961 of the Nrf2 promoter region in renal cell cancer
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DOI：
10.1186/s12885-019-6347-0
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发表时间：
2019-11-21
期刊：
影响因子：
3.8
通讯作者：
Yoshida, Ken-Ichiro
中科院分区：
文献类型：
--
作者：
Yamaguchi, Yoshiyuki;Kamai, Takao;Yoshida, Ken-Ichiro
背景核因子红系2相关因子2(Nrf2)通过促进代谢活性参与细胞增殖。它也是抗氧化剂的主要调节剂，在肿瘤细胞的增殖和对化疗的耐药性中起着关键作用。因此，我们研究了Nrf2在肾癌中的作用。方法对50例接受细胞减少性肾切除术的转移性肾癌患者进行Nrf2基因突变分析，同时检测Nrf2启动子区域的单核苷酸多态(SNP；rs6721961)及其蛋白表达。结果靶向下一代测序显示，5例肿瘤存在与氨基酸序列变异相关的Nrf2基因SNPs，11例肿瘤存在Kelch样ECH相关蛋白1基因SNPs，35例存在von Hippel-Lindau基因SNPs，无一例存在富马酸水合酶基因SNPs。Rs6721961的C/C、C/A和A/A三种基因频率分别为60%、34%和6%。Nrf2基因突变和C/A或A/A基因与Nrf2蛋白表达增加显著相关(p=0.0184和p=0.0005)。当原发肿瘤出现NRF2基因突变、C/A或A/A基因型或NRF2蛋白表达升高时，转移瘤对血管内皮生长因子靶向治疗的反应明显较差(分别为p=0.0142，p=0.0018，p=0.0001)，总生存率显著降低(分别为p=0.0343，p=0.0421，p<；0.0001)。根据多变量COX比例分析，Nrf2蛋白表达升高也与较短的生存期相关。结论提示肾细胞癌的进展与Nrf2信号转导有关。
Background Nuclear factor erythroid 2-related factor 2 (Nrf2) is involved in cell proliferation by promotion of metabolic activity. It is also the major regulator of antioxidants and has a pivotal role in tumor cell proliferation and resistance to chemotherapy. Accordingly, we investigated the role of Nrf2 in renal cell carcinoma (RCC). Methods In 50 patients who had metastatic RCC and received cytoreductive nephrectomy, we performed Nrf2 gene mutation analysis using targeted next-generation sequencing, as well as investigating a specific single nucleotide polymorphism (SNP; rs6721961) in the Nrf2 promoter region and Nrf2 protein expression. Results Targeted next-generation sequencing revealed that five tumors had SNPs of Nrf2 associated with amino acid sequence variation, while 11 tumors had SNPs of Kelch-like ECH-associated protein 1 gene, 35 had SNPs of von Hippel-Lindau gene, and none had SNPs of fumarate hydratase gene. The three genotypes of rs6721961 showed the following frequencies: 60% for C/C, 34% for C/A, and 6% for A/A. Nrf2 mutation and the C/A or A/A genotypes were significantly associated with increased Nrf2 protein expression (p = 0.0184 and p = 0.0005, respectively). When the primary tumor showed Nrf2 gene mutation, the C/A or A/A genotype, or elevated Nrf2 protein expression, the response of metastases to vascular endothelial growth factor-targeting therapy was significantly worse (p = 0.0142, p = 0.0018, and p < 0.0001, respectively), and overall survival was significantly reduced (p = 0.0343, p = 0.0421, and p < 0.0001, respectively). Elevated Nrf2 protein expression was also associated with shorter survival according to multivariate Cox proportional analysis. Conclusion These findings suggest an associated between progression of RCC and Nrf2 signaling.