Pulmonary Neuroendocrine Carcinomas Show Alteration of Nrf2/Keap1 Pathway.
Konstantin Shilo, Wei-Sing Chu, Jin Jen, William Travis, Teri Franks, Charles Hitchcock, Weiqiang Zhao, Ramesh Ganju. OSU, Columbus, OH; AFIP, Washington, DC; Mayo Clinic, Rochester, MN; MSKCC, New York, NY
Background: Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates expression of molecules involved in cellular protection from toxins, oxidative stress and chemicals. Nrf2 expression is repressed by Kelch-like ECH associated protein 1 (Keap1). Phosphorylation of Nrf2 at serine-40 has been shown to mediate a dissociation of Nrf2 from Keap1, therefore playing a critical role in regulating Nrf2/Keap1 pathway. Although, recently Nrf2/Keap1 alterations have been reported in non-small cell lung carcinomas (NSCLC), not much is known about this pathway in neuroendocrine carcinomas (NEC). The aim of this study was to investigate expression of phosphorylated Nrf2 and Keap1 in a wide range of pulmonary NEC and assess their possible association with clinical-pathological findings.
Design: Clinical pathological findings of 178 patients were analyzed with regard to Nrf2 and Keap1 expression. Tissue microarray based samples of 48 typical carcinoids (TC), 31 atypical carcinoids (AC), 27 large cell neuroendocrine carcinomas (LCNEC), and 72 small cell lung carcinomas (SCLC) were studied for phosphorylated Nrf2 using antibody that recognizes phosphoserine residue located at amino-acid 40 (1:500, EP1809Y, Epitomics, Burlingame, CA) and for Keap1 (1:200, poly, ProteinTech, Chicago, IL). The staining was evaluated in comparison to normal lung parenchyma and recorded as negative, cytoplasmic, and nuclear with stratification of intensity as high versus low.
Results: Phospho-Nrf2 was localized to the nucleus and was detected in 76.2% (125/164) of NEC. High levels of phospho-Nrf2 were seen in 27.9% of TC, 37.9% of AC, 76.9% of LCNEC and 73.4% of SCLC. Nrf2 expression strongly correlated with tumor grade (p<.001) but not with patient's age, gender, tumor size, stage or outcome. Keap1 expression was seen in cytoplasm and at high levels was observed in 34.6% (56/162) of NEC. High levels of Keap1 were detected in 26.1% of TC, 31.0% of AC, 26.1% of LCNEC and 45.3% of SCLC. There was a trend towards a better outcome in NEC with negative Keap1 (p=.1).
Conclusions: Phosphorylated Nrf2 is observed in a significant percentage of pulmonary NEC and shows strong correlation with NEC grade with most frequent expression at high levels in LCNEC and SCLC. Keap1 expression may have prognostic significance in NEC similar to what is known in NSCLC. These studies suggest a possible involvement of the Keap1/Nrf2 pathway in NEC pathogenesis.
Wednesday, March 2, 2011 9:30 AM
Poster Session V # 247, Wednesday Morning