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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

Schematic illustration of the main findings of the present study.NF-κB subunit expression levels in tumor and stroma cells of 77 patients with NSCLC are indicated by relative font size. Arrows indicate possible associations of Rel protein expression levels in NSCLC tumor cells with tumor-associated inflammation and cellular proliferation.
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pone.0132527.g006: Schematic illustration of the main findings of the present study.NF-κB subunit expression levels in tumor and stroma cells of 77 patients with NSCLC are indicated by relative font size. Arrows indicate possible associations of Rel protein expression levels in NSCLC tumor cells with tumor-associated inflammation and cellular proliferation.

Mentions: In the present study, we characterized the expression and the subcellular localization of several NF-κB subunits in human NSCLC and experimental models of the disease. We found different patterns of immunoreactivity for each of the subunits studied, justifying our integrated approach. In specific, RelB was highly expressed in tumor cells, while RelA and P50 in stromal cells. Interestingly, tumor RelA expression was correlated with inflammatory infiltration and tumor RelB expression was collocalized with proliferating tumor cell nuclei. These results were consistent with binary logistic regression analyses that revealed that tumor RelA expression was an independent predictor of inflammatory infiltrates, while tumor RelB immunoreactivity predicted more advanced disease with nodal involvement. Finally, this pattern of predominant RelB expression in human NSCLC was recapitulated in mouse models of the disease. Collectively, our results indicate a multi-modal activation of NF-κB in NSCLC and possibly suggest divergent functions for RelA and RelB in driving paracrine induction of inflammation and cell-autonomous or autocrine promotion of cellular proliferation, respectively (Fig 6).


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)

Schematic illustration of the main findings of the present study.NF-κB subunit expression levels in tumor and stroma cells of 77 patients with NSCLC are indicated by relative font size. Arrows indicate possible associations of Rel protein expression levels in NSCLC tumor cells with tumor-associated inflammation and cellular proliferation.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0132527.g006: Schematic illustration of the main findings of the present study.NF-κB subunit expression levels in tumor and stroma cells of 77 patients with NSCLC are indicated by relative font size. Arrows indicate possible associations of Rel protein expression levels in NSCLC tumor cells with tumor-associated inflammation and cellular proliferation.
Mentions: In the present study, we characterized the expression and the subcellular localization of several NF-κB subunits in human NSCLC and experimental models of the disease. We found different patterns of immunoreactivity for each of the subunits studied, justifying our integrated approach. In specific, RelB was highly expressed in tumor cells, while RelA and P50 in stromal cells. Interestingly, tumor RelA expression was correlated with inflammatory infiltration and tumor RelB expression was collocalized with proliferating tumor cell nuclei. These results were consistent with binary logistic regression analyses that revealed that tumor RelA expression was an independent predictor of inflammatory infiltrates, while tumor RelB immunoreactivity predicted more advanced disease with nodal involvement. Finally, this pattern of predominant RelB expression in human NSCLC was recapitulated in mouse models of the disease. Collectively, our results indicate a multi-modal activation of NF-κB in NSCLC and possibly suggest divergent functions for RelA and RelB in driving paracrine induction of inflammation and cell-autonomous or autocrine promotion of cellular proliferation, respectively (Fig 6).

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