Nrf2 and Keap1 abnormalities in non-small cell lung carcinoma and association with clinicopathologic features.
Nrf2 and Keap1 abnormalities in non-small cell lung carcinoma and association with clinicopathologic features.
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DOI：
10.1158/1078-0432.ccr-09-3352
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发表时间：
2010-07-15
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影响因子：
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通讯作者：
Wistuba II
中科院分区：
文献类型：
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作者：
Solis LM;Behrens C;Dong W;Suraokar M;Ozburn NC;Moran CA;Corvalan AH;Biswal S;Swisher SG;Bekele BN;Minna JD;Stewart DJ;Wistuba II
为了了解Nrf2和Keap1在NSCLC中的作用，我们研究了它们在一大系列肿瘤中的表达，这些肿瘤具有注释的临床病理数据，包括对铂类辅助化疗的反应。我们检测了304例NSCLC和89例接受新辅助化疗(n=26)或辅助铂类化疗(n=63)的NSCLC中Nrf2和Keap1的免疫组织化学表达及其与临床病理特征的关系。我们对31例肿瘤标本进行了NFE2L2和Keap1突变检测。我们在26%的非小细胞肺癌中检测到NRF2的核表达；它在鳞癌中的表达(38%)明显高于腺癌(18%；P<；0.0001)。56%的NSCLC中低表达或不表达Keap1；腺癌(62%)明显高于鳞癌(46%；P=0.0057)。在非小细胞肺癌中，NFE2L2和Keap1突变非常罕见(29例中有2例，31例中有1例)。多因素分析显示，NRF2的表达与非小细胞肺癌患者的总生存期相关(P=0.0139；HR=1.75)，而Keap1的低表达或缺失与鳞癌的总生存期相关(P=0.0181；HR=2.09)。单因素分析显示，在接受辅助治疗的鳞癌患者中，Nrf2的核表达与患者的无复发生存率相关(P=0.0410；HR=3.37)。Nrf2的高表达和Keap1的低表达是NSCLC中常见的异常，并与不良预后相关。恶性肺癌细胞中Nrf2的核表达可能在鳞癌对铂类药物耐药中起作用。
To understand the role of Nrf2 and Keap1 in NSCLC, we studied their expression in a large series of tumors with annotated clinicopathologic data, including response to platinum-based adjuvant chemotherapy. We determined the immunohistochemical expression of nuclear Nrf2 and cytoplasmic Keap1 in 304 NSCLCs and its association with patients’ clinicopathologic characteristics, and in 89 tumors from patients who received neoadjuvant (n=26) or adjuvant platinum-based chemotherapy (n=63). We evaluated NFE2L2 and KEAP1 mutations in 31 tumor specimens. We detected nuclear Nrf2 expression in 26% of NSCLCs; it was significantly more common in squamous cell carcinomas (38%) than in adenocarcinomas (18%; P<0.0001). Low or absent Keap1 expression was detected in 56% of NSCLCs; it was significantly more common in adenocarcinomas (62%) than in squamous cell carcinomas (46%; P=0.0057). In NSCLC, mutations of NFE2L2 and KEAP1 were very uncommon (2 of 29 and 1 of 31 cases, respectively). In multivariate analysis, Nrf2 expression was associated with worse overall survival (P=0.0139; HR=1.75) in NSCLC patients, and low or absent Keap1 expression was associated with worse overall survival (P=0.0181; HR=2.09) in squamous cell carcinoma. In univariate analysis, nuclear Nrf2 expression was associated with worse recurrence-free survival in squamous cell carcinoma patients who received adjuvant treatment (P=0.0410; HR=3.37). Increased expression of Nrf2 and decreased expression of Keap1 are common abnormalities in NSCLC and are associated with a poor outcome. Nuclear expression of Nrf2 in malignant lung cancer cells may play a role in resistance to platinum-based treatment in squamous cell carcinoma.