Research Article: The association and prognostic impact of enhancer of zeste homologue 2 expression and epithelial–mesenchymal transition in resected lung adenocarcinoma

Date Published: May 1, 2019

Publisher: Public Library of Science

Author(s): Taichi Matsubara, Gouji Toyokawa, Kazuki Takada, Fumihiko Kinoshita, Yuka Kozuma, Takaki Akamine, Mototsugu Shimokawa, Akira Haro, Atsushi Osoegawa, Tetsuzo Tagawa, Masaki Mori, Masaru Katoh.

http://doi.org/10.1371/journal.pone.0215103

Abstract

Epithelial-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.

EZH2 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.

We 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.

EMT and high EZH2 expression were associated with poor NSCLC prognoses. Vimentin is a key factor linking EMT and EZH2 in lung adenocarcinoma.

Partial Text

Lung cancer is the leading cause of cancer-related death worldwide. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, representing 85% of all cases, and is classified into several subtypes, including adenocarcinoma and squamous cell carcinoma[1]. The discovery of oncogenic driver mutations and their targeted therapies have become the forefront of NSCLC treatment[2, 3]. Furthermore, immune checkpoint inhibitors have emerged as a novel therapeutic strategy for NSCLC[4, 5]. Thus, therapeutic options for NSCLC have changed dramatically, and prognoses have improved compared with previous decades.

EMT is a crucial phenotypic change that facilitates tumor invasion and progression, and is associated with poor survival in NSCLC patients [17, 20]. EZH2 is an important factor associated with aggressive tumor behavior, advanced stage, and poor survival in NSCLC [12]. Several studies have investigated associations between EMT and EZH2; however, no studies have examined their correlation by IHC, nor have any determined their combined prognostic impact. Importantly, our study showed a significant correlation between EZH2 expression and EMT, and furthermore, demonstrated combined effects of EZH2 and EMT on survival in clinical lung adenocarcinoma specimens. In particular, the EMT marker Vimentin plays a key role linking EMT and EZH2.

 

Source:

http://doi.org/10.1371/journal.pone.0215103

 

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