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

Giopanou I, Lilis I, Papaleonidopoulos V, Marazioti A, Spella M, Vreka M, Papadaki H, Stathopoulos GT - PLoS ONE (2015)

Bottom Line: We found that the expression of the different NF-κB subunits was not concordant, warranting our integral approach.Overall, RelA, RelB, and P50 were expressed at higher levels compared with P52/P100.We conclude that pathologic studies of NF-κB expression in cancer should include multiple pathway components.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Achaia, Greece.

ABSTRACT
Nuclear factor (NF)-κB signalling is required for lung adenocarcinoma development in mice, and both of its subunits RelA and RelB 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 RelA, RelB, 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, RelA, RelB, and P50 were expressed at higher levels compared with P52/P100. However, RelA and P50 were predominantly expressed in intratumoral stroma, but RelB in tumor cells. Importantly, tumor area RelA expression was correlated with the intensity of inflammatory infiltration, whereas RelB expression was identified in proliferating tumor cells. Using multiple logistic regression, we identified that tumor RelB expression was an independent predictor of lymph node metastasis, and tumor P50 was an independent predictor of TNM6 stage IIB or higher, whereas tumor RelA 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.

No MeSH data available.


Related in: MedlinePlus

Immunohistochemical detection of NF-κB in mouse models of NSCLC.NF-κB subunit expression was assessed by immunohistochemistry in urethane-induced mouse lung adenomas (A and C) and mutant KRAS-induced lung adenocarcinomas (B and D). (A, B) Representative images. (C, D) Overall scoring of NF-κB subunit expression levels from four mice per group. Data presented as mean ± SD. ** and ***: P < 0.01, and P < 0.001 for the indicated color-coded subunit compared with normal bronchial and alveolar epithelium by two-way ANOVA followed by Bonferroni post-tests. Non-significant comparisons are not indicated.
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pone.0132527.g005: Immunohistochemical detection of NF-κB in mouse models of NSCLC.NF-κB subunit expression was assessed by immunohistochemistry in urethane-induced mouse lung adenomas (A and C) and mutant KRAS-induced lung adenocarcinomas (B and D). (A, B) Representative images. (C, D) Overall scoring of NF-κB subunit expression levels from four mice per group. Data presented as mean ± SD. ** and ***: P < 0.01, and P < 0.001 for the indicated color-coded subunit compared with normal bronchial and alveolar epithelium by two-way ANOVA followed by Bonferroni post-tests. Non-significant comparisons are not indicated.

Mentions: We finally sought to verify whether our findings could also be recapitulated in two different mouse models of human NSCLC, namely the model of urethane-induced pulmonary adenoma and of mutant KRAS-induced pulmonary adenocarcinoma. Analyses, done as for human samples, identified that RelB was overexpressed in urethane-induced hyperplastic lesions, but not in adenomas. Moreover, RelB was overexpressed in both mutant KRAS-induced hyperplastic lesions and adenocarcinomas (Fig 5). These findings were consistent with the human data showing focal overexpression of RelB in tumor areas of human NSCLC (Fig 2).


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

Giopanou I, Lilis I, Papaleonidopoulos V, Marazioti A, Spella M, Vreka M, Papadaki H, Stathopoulos GT - PLoS ONE (2015)

Immunohistochemical detection of NF-κB in mouse models of NSCLC.NF-κB subunit expression was assessed by immunohistochemistry in urethane-induced mouse lung adenomas (A and C) and mutant KRAS-induced lung adenocarcinomas (B and D). (A, B) Representative images. (C, D) Overall scoring of NF-κB subunit expression levels from four mice per group. Data presented as mean ± SD. ** and ***: P < 0.01, and P < 0.001 for the indicated color-coded subunit compared with normal bronchial and alveolar epithelium by two-way ANOVA followed by Bonferroni post-tests. Non-significant comparisons are not indicated.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493092&req=5

pone.0132527.g005: Immunohistochemical detection of NF-κB in mouse models of NSCLC.NF-κB subunit expression was assessed by immunohistochemistry in urethane-induced mouse lung adenomas (A and C) and mutant KRAS-induced lung adenocarcinomas (B and D). (A, B) Representative images. (C, D) Overall scoring of NF-κB subunit expression levels from four mice per group. Data presented as mean ± SD. ** and ***: P < 0.01, and P < 0.001 for the indicated color-coded subunit compared with normal bronchial and alveolar epithelium by two-way ANOVA followed by Bonferroni post-tests. Non-significant comparisons are not indicated.
Mentions: We finally sought to verify whether our findings could also be recapitulated in two different mouse models of human NSCLC, namely the model of urethane-induced pulmonary adenoma and of mutant KRAS-induced pulmonary adenocarcinoma. Analyses, done as for human samples, identified that RelB was overexpressed in urethane-induced hyperplastic lesions, but not in adenomas. Moreover, RelB was overexpressed in both mutant KRAS-induced hyperplastic lesions and adenocarcinomas (Fig 5). These findings were consistent with the human data showing focal overexpression of RelB in tumor areas of human NSCLC (Fig 2).

Bottom Line: We found that the expression of the different NF-κB subunits was not concordant, warranting our integral approach.Overall, RelA, RelB, and P50 were expressed at higher levels compared with P52/P100.We conclude that pathologic studies of NF-κB expression in cancer should include multiple pathway components.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Achaia, Greece.

ABSTRACT
Nuclear factor (NF)-κB signalling is required for lung adenocarcinoma development in mice, and both of its subunits RelA and RelB 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 RelA, RelB, 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, RelA, RelB, and P50 were expressed at higher levels compared with P52/P100. However, RelA and P50 were predominantly expressed in intratumoral stroma, but RelB in tumor cells. Importantly, tumor area RelA expression was correlated with the intensity of inflammatory infiltration, whereas RelB expression was identified in proliferating tumor cells. Using multiple logistic regression, we identified that tumor RelB expression was an independent predictor of lymph node metastasis, and tumor P50 was an independent predictor of TNM6 stage IIB or higher, whereas tumor RelA 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.

No MeSH data available.


Related in: MedlinePlus