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Nuclear factor (NF)-κB signalling is required for lung adenocarcinoma development in mice, and both of its subunits  Rel A and  Rel B were independently reported to be highly expressed in human non-small cell lung cancer (NSCLC). To comprehensively examine NF-κB expression in NSCLC, we analyzed serial sections of primary tumor samples from 77 well-documented patients (36 adenocarcinomas, 40 squamous cell carcinomas and 3 large cell carcinomas) for immunoreactivity of  Rel A,  Rel B, P50, and P52/P100. Tumor and intratumoral stroma areas were discriminated based on proliferating cell nuclear antigen immunoreactivity and inflammatory infiltration was assessed in intratumoral stroma areas. NF-κB immunoreactivity was quantified by intensity, extent, and nuclear localization and was cross-examined with tumor cell proliferation, inflammatory infiltration, and clinical-pathologic data. We found that the expression of the different NF-κB subunits was not concordant, warranting our integral approach. Overall,  Rel A,  Rel B, and P50 were expressed at higher levels compared with P52/P100. However,  Rel A and P50 were predominantly expressed in intratumoral stroma, but  Rel B in tumor cells. Importantly, tumor area  Rel A expression was correlated with the intensity of inflammatory infiltration, whereas  Rel B expression was identified in proliferating tumor cells. Using multiple logistic regression, we identified that tumor  Rel B expression was an independent predictor of lymph node metastasis, and tumor P50 was an independent predictor of TNM6 stage IIB or higher, whereas tumor  Rel A was an independent predictor of inflammatory infiltration. We conclude that pathologic studies of NF-κB expression in cancer should include multiple pathway components. Utilizing such an approach, we identified intriguing associations between distinct NF-κB subunits and clinical and pathologic features of NSCLC.

Comprehensive Evaluation of Nuclear Factor-κΒ Expression Patterns in Non-Small Cell Lung Cancer