Nrf2 and Keap1 Abnormalities in Non-Small Cell Lung Carcinoma and Association with Clinicopathologic Features

被引：365

作者：

Solis, Luisa M.

Behrens, Carmen ^{[2
]}

Dong, Wenli ^{[3
]}

Suraokar, Milind ^{[2
]}

Ozburn, Natalie C. ^{[2
]}

Moran, Cesar A.

Corvalan, Alejandro H. ^{[2
]}

Biswal, Shyam ^{[8
]}

Swisher, Stephen G. ^{[4
]}

Bekele, B. Nebiyou ^{[3
]}

Minna, John D. ^{[5
,6
,7
]}

Stewart, David J. ^{[2
]}

Wistuba, Ignacio I. ^{[1
,2
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Unit 85, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX 77030 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Thorac Surg, Houston, TX 77030 USA

[5] Univ Texas SW Med Ctr Dallas, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75390 USA

[6] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA

[7] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA

[8] Johns Hopkins Univ, Dept Environm Hlth Sci, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA

来源：

CLINICAL CANCER RESEARCH | 2010年 / 16卷 / 14期

关键词：

GROWTH-FACTOR RECEPTOR; HEME OXYGENASE-1; CANCER; MUTATIONS; EXPRESSION; ACTIVATION; FACTOR-2; PROTEIN; STAGE; GENE;

D O I：

10.1158/1078-0432.CCR-09-3352

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: 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. Experimental Design: 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. Results: 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). Conclusions: 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. Clin Cancer Res; 16(14); 3743-53. (C)2010 AACR.

引用

页码：3743 / 3753

页数：11

共 34 条

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