The association and prognostic impact of enhancer of zeste homologue 2 expression and epithelial-mesenchymal transition in resected lung adenocarcinoma.

ObjectivesEpithelial-mesenchymal transition (EMT) and the histone methyltransferase Enhancer of Zeste Homologue 2 (EZH2) are important regulators of lung cancer progression and metastasis. Although recent studies support the correlation between EZH2 expression and EMT, no reports have investigated their association using immunohistochemistry or explored their prognostic impact on lung adenocarcinoma. The aim of this study was to elucidate the association between EZH2 and EMT, and their prognostic significance.MethodsEZH2 and the EMT markers E-cadherin and Vimentin were examined by IHC in lung adenocarcinoma specimens that were resected from 2003-2012. Associations between EZH2 and EMT markers and their correlations with survival were analyzed.ResultsWe enrolled 350 patients, approximately 70% of whom were diagnosed as pathological stage I. The rates of positive E-cadherin, Vimentin, and EZH2 expression were 60.3%, 21.4%, and 52.0%, respectively. There was a significant positive correlation between EZH2 and Vimentin expression (p = 0.008), and EZH2 scores were higher in the Mesenchymal group (p = 0.030). In multivariate analysis, EZH2 was an independent predictor of Vimentin expression, and vice versa. EMT and EZH2 overexpression were significantly correlated with poor disease-free and overall survival. Furthermore, the Epithelial group with high EZH2 expression had significantly worse disease-free and overall survival. Positive staining for EMT markers was unfavorable regarding disease-free survival among patients with low EZH2 expression.ConclusionsEMT and high EZH2 expression were associated with poor NSCLC prognoses. Vimentin is a key factor linking EMT and EZH2 in lung adenocarcinoma

Clinical implications of the novel cytokine IL-38 expressed in lung adenocarcinoma: Possible association with PD-L1 expression.

Interleukin (IL)-38, a novel member of the IL-1 cytokine family, is homologous to IL-1 receptor antagonist (IL-1Ra) and IL-36Ra, and has been reported to act as an antagonist. IL-38 expression is found in tonsil, placenta, and spleen, and recent studies suggest an association between IL-38 and autoimmune diseases. However, whether IL-38 plays a role in carcinogenesis or cancer growth is unclear. In the present study, we identified increases in IL-38 expression by immunohistochemistry in multiple types of cancer cells. In the examination of 417 surgically resected primary lung adenocarcinomas, Fisher's exact tests showed significant associations between high IL-38 expression and high tumor grades, an advanced T status, advanced N status, advanced stage, and the presence of pleural and vessel invasions. Survival analyses by the Kaplan-Meier method showed that patients with high expression of IL-38 had significantly shorter disease-free survival and shorter overall survival after surgery than patients with low expression of IL-38 (log-rank test: P = 0.0021 and P = 0.0035, respectively). Moreover, programmed cell death-ligand 1 (PD-L1)-positive cases showed higher expression of IL-38 than PD-L1-negative cases (Wilcoxon rank-sum test: P < 0.0001). In conclusion, IL-38 was expressed in tumor cells of various cancers, and IL-38 expression was associated with poor survival of lung adenocarcinoma patients. IL-38 may affect host immunity or the tumor microenvironment, and contribute to the progression of lung adenocarcinoma

Clinicopathological characteristics of patients with primary lung adenocarcinoma.

<p>Clinicopathological characteristics of patients with primary lung adenocarcinoma.</p

Association between IL-38 expression and clinicopathological factors in patients with primary lung adenocarcinoma.

<p>Association between IL-38 expression and clinicopathological factors in patients with primary lung adenocarcinoma.</p

Association between PD-L1 and IL-38 expression.

<p>(A) PD-L1-positive cases showed higher expression of IL-38 than PD-L1-negative cases (Wilcoxon rank-sum test: <i>P</i> < 0.0001). (B) Representative images of (upper panel) PD-L1 staining and (lower panel) IL-38 staining in a (left panel) PD-L1-negative case and (right panel) PD-L1-positive case. IHC: immunohistochemistry, PD-L1: programmed cell death-ligand 1, IL-38: interleukin-38. Scale bar: 100 μm.</p

Representative images of (left panel) HE staining, (middle panel) IL-38 staining, and (right panel) negative controls.

<p>(A) Human tonsil tissue. (B) Human placenta tissue. (C) Human spleen tissue. HE: Hematoxylin-eosin, IL-38: interleukin-38. Scale bar: 100 μm.</p

Kaplan-Meier curves according to IL-38 expression in the analysis of PD-L1-negative cases and PD-L1-positive cases.

<p>Kaplan-Meier curves showing (A, C) disease-free and (B, D) overall survival of primary lung adenocarcinoma patients according to IL-38 expression in the analysis of (A, B) PD-L1-negative cases and (C, D) PD-L1-positive cases. IL-38: interleukin-38, PD-L1: programmed cell death-ligand 1.</p

Univariate and multivariate analyses of the relationship between IL-38 expression and other patient characteristics.

<p>Univariate and multivariate analyses of the relationship between IL-38 expression and other patient characteristics.</p

Univariate and multivariate analyses of DFS and OS in patients with primary lung adenocarcinoma.

<p>Univariate and multivariate analyses of DFS and OS in patients with primary lung adenocarcinoma.</p