Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Clin Cancer Res. 2010 Jul 15;16(14):3743-53. doi: 10.1158/1078-0432.CCR-09-3352. Epub 2010 Jun 9.
To understand the role of nuclear factor erythroid-2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) in non-small cell lung cancer (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; hazard ratio (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.
为了了解核因子红细胞 2 相关因子 2（Nrf2）和 Kelch 样 ECH 相关蛋白 1（Keap1）在非小细胞肺癌（NSCLC）中的作用，我们研究了它们在具有注释临床病理数据的大型肿瘤系列中的表达情况，包括对铂类辅助化疗的反应。
我们测定了 304 例 NSCLC 中核 Nrf2 和细胞质 Keap1 的免疫组化表达情况，并与患者的临床病理特征相关联，同时还与接受新辅助（n=26）或辅助铂类化疗（n=63）的 89 例肿瘤相关联。我们评估了 31 个肿瘤标本中的 NFE2L2 和 KEAP1 突变。
我们在 26%的 NSCLC 中检测到核 Nrf2 的表达；在鳞癌中更为常见（38%），而在腺癌中则较少见（18%；P＜0.0001）。在 56%的 NSCLC 中检测到低表达或无表达的 Keap1；在腺癌中更为常见（62%），而在鳞癌中则较少见（46%；P=0.0057）。在 NSCLC 中，NFE2L2 和 KEAP1 的突变非常罕见（分别为 2 例和 1 例）。多因素分析显示，Nrf2 的表达与 NSCLC 患者的总生存时间较差相关（P=0.0139；风险比[HR]，1.75），而低表达或无表达的 Keap1 与鳞癌患者的总生存时间较差相关（P=0.0181；HR，2.09）。在单因素分析中，核 Nrf2 的表达与接受辅助治疗的鳞癌患者的无复发生存时间较差相关（P=0.0410；HR，3.37）。
Nrf2 的表达增加和 Keap1 的表达降低是 NSCLC 的常见异常现象，与预后不良相关。恶性肺癌细胞中核 Nrf2 的表达可能在鳞癌中对铂类治疗的耐药性中起作用。
