Nrf2、Keap1蛋白在104例肺腺癌中的表达及其临床病理特征

Nrf2 and Keap1 Abnormalities in 104 Lung Adenocarcinoma Cases and Association with Clinicopathologic Features

背景与目的前期研究表明核因子E2相关因子2(nuclear factor erythroid-2-related factor 2,Nrf2)和Kelch样环氧氯丙烷相关蛋白1(Kelch-like ECH-associated protein 1,Keap1)的表达在肺癌患者中存在个体差异,其与化疗或表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor tyrosine kinase inhibitors,EGFR-TKIs)的疗效相关,但Nrf2及Keap1在不同驱动基因肺腺癌患者中的表达情况仍不清楚。本研究旨在探讨Nrf2、Keap1在肺腺癌患者中的表达与EGFR基因突变状态的关系及其对EGFR-TKIs疗效的影响。方法应用免疫组化方法检测104例EGFR结果明确的肺腺癌患者,确定Nrf2、Keap1的表达情况,并分析其临床病理特征。结果 104例患者中Nrf2阳性率为71.2%,Keap1高表达率为34.6%;Nrf2阳性率与性别、分期和EGFR突变状态显著相关(P<0.05),而与年龄、吸烟、分化程度、病理亚型无关(P>0.05);Keap1表达水平与年龄、性别、吸烟、病理亚型、肿瘤分化、EGFR突变状态等均无关(P>0.05);EGFR-TKIs治疗的患者无进展生存期(progression free survival,PFS)和总生存期(overall survival,OS)与Nrf2表达水平显著相关(P>0.05),但与Keap1表达水平无关(P<0.05)。Nrf2高表达组的中位PFS、OS显著低于低表达/阴性组(P<0.05)。多因素分析表明Nrf2表达水平是EGFR-TKIs PFS和OS的独立预测因素。结论Nrf2阳性率与EGFR基因突变状态显著相关,Nrf2在EGFR突变肺腺癌患者中的表达水平与EGFR TKIs疗效显著相关,因此,Nrf2是预测EGFR TKIs疗效的理想指标和潜在的干预靶点。

Background and objective There are significantly interindividual variations of the expression level of nuclear factor erythroid-2-related factor 2 （Nrf2） and/or Kelch-like ECH-associated protein 1 （Keap1） in our previous studies. It has been proven that Nrf2 or Keapl is related to resistance of chemotherapeutic drugs and/or epidermal growth factor receptor tyrosine kinase inhibitors （EGFR-TKIs）. However, the expression of Nrf2 and Keap1 in lung adenocarcinoma patients with different ＂driver gene＂ is not clear. The aim of this study is to investigate the protein expression level of Nrf2 and Keap1 in lung adenocarcinoma and to elucidate the correlation between Nrf2 or Keapl expression and the status of EGFR gene mutation and to determine the effects of Nrf2 and Keapl on the patients. Methods Immunohistochemical analysis of Nrf2 and Keapl in tumor specimens was performed in a total of 104 lung adenocarcinoma patients with the status of EGFR gene mutations or EGFR wide-type. Results The Nrf2 positive rate was 71.2% and Keapl high expression rate was 34.6% in 104 patients. The Nrf2 positive rate significantly correlated with gender, stage and status ofEGFR gene mutation （P〈0.05）, but not with age, smoking, differentiation and subtype of lung adenocarcinoma （P〉0.05）. The high expression of Keapl was not significantly correlated with gender, age, smoking, differentiation, subtype of lung adenocarcinoma and status of EGFR gene mutation （P〉0.05）. The progression -free survival （PFS） and overall survival （OS） of the patients treated by EGFR-TKIs were significantly correlated with the expression level of Nrf2, but not with Keapl. The PFS and OS of the patients with Nrf2 high expression were significantly shorter than the patients with low/negative expression （P〈0.05）. Furthermore, Nrf2 high expression was the independent predictive factor for EGFR-TKIs induced PFS and OS （P〈0.05）. Conclusion The Nrf2 positive rate significantly correlated with the status ofEGFR gene mutation in lung adenocarcinoma, The Nrf2 high expression significantly correlated with PFS and OS of EGFR-TKIs. Therefore, Nrf2 may be a biomarker for predicting response of EGFR-TKIs and a potential target for overcoming resistance of EGFR-TKIs.