Phosphorylated Mnk1 and eIF4E Are Associated with Lymph Node Metastasis and Poor Prognosis of Nasopharyngeal Carcinoma

Jun Zheng,Guiyuan Xie,Lina Xu,Duo Li,Songqing Fan,Jiao Li,Donghai Huang,Jiadi Luo,Qiuyuan Wen,Irina V Lebedeva

doi:10.1371/journal.pone.0089220

Abstract

Nasopharyngeal carcinoma (NPC) is a head and neck malignant tumor rare throughout most of the world but common in Southeast Asia, especially in Southern China. The phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) by MAP kinase-interacting kinases (Mnk) on Ser-209 promotes cellular proliferation, survival, malignant transformation and metastasis. However, whether the alterations of the expression of p-eIF4E and p-Mnk1 protein are associated with clinicopathologic/prognostic implication for NPC has not been reported. The purposes of the present study are to examine the expression of p-eIF4E and p-Mnk1 protein in NPC and non-cancerous nasopharyngeal epithelial tissues by immunohistochemistry and evaluate the association between the expression of p-eIF4E and p-Mnk1 protein and clinicopathological characteristics of NPC. The results showed that the positive percentage of p-Mnk1 and p-eIF4E proteins expression in NPC (83.5% and 75.4%, respectively) was significantly higher than that in non-cancerous nasopharyngeal epithelium (40.0% and 32.9%, respectively). The positive expression of p-eIF4E and p-Mnk1 in the NPC with cervical lymph node metastasis was significantly higher than those without lymph node metastasis. Additionally, p-eIF4E expression was more pronouncedly increased in metastatic NPC than the matched primary NPC. Increase of p-eIF4E and p-Mnk1 expression was significantly correlated inversely with overall survival. Spearman’s rank correlation test further showed that expression of p-Mnk1 was strongly positive correlated with expression of p-eIF4E in NPC. The expression of p-Mnk1 and p-eIF4E in NPC was proved to be the independent prognostic factors regardless of lymph node metastasis, clinical stages and combination of radiotherapy and chemotherapy, histological type, age and gender by multivariate analysis. Taken together, high expression of p-Mnk1 and p-eIF4E might be novel valuable biomarkers to predict poor prognosis of NPC and therapeutic targets for developing the valid treatment strategies.

Highlights

Nasopharyngeal carcinoma (NPC) is a head and neck malignant tumor rare throughout most of the world but common in Southeast Asia, especially in Southern China [1]
We analyzed the associations between the p-Mnk1 and peIF4E expression and clinicopathological features of NPC patient including age, gender, histological type, clinical stages, cervical lymph node metastasis, and survival status by univariate ChiSquare Test
Increasing evidences have shown that MAP kinase-interacting kinases (Mnk) and eukaryotic translation initiation factor 4E (eIF4E) play important roles in the pathogenesis and prognosis of many tumors

Summary

Introduction

Nasopharyngeal carcinoma (NPC) is a head and neck malignant tumor rare throughout most of the world but common in Southeast Asia, especially in Southern China [1]. Eukaryotic translation initiation factor 4E (eIF4E) plays a critical role in initiating translation of mRNAs, and up-regulating the expression of tumor relevant proteins, which are involved in activation of proto-oncogenes, angiogenesis, autocrine growth stimulation, cell survival, invasion and communication with the extracellular environment [8,9,10,11,12,13]. Overexpression and/or increased phosphorylation of eIF4E, considered to be a proto-oncogene, leads to PLOS ONE | www.plosone.org p-Mnk and p-eIF4E Associated with NPC Prognosis overexpression of certain proto-oncogenes, growth factors, and other cell cycle–related protein transcripts, which promotes proliferation and survival rate of tumor cell and effectively regulates cellular transformation and metastasis [9,20,24,26,27]. Some studies have shown that p-eIF4E and p-Mnk were respectively correlated with human carcinogenesis and development, and the inhibition of the Mnk1/eIF4E pathway acted as a potential therapeutic target [9,10,13,24,27,28,29,30,31]

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Results

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