Increased expression of flotillin-2 protein as a novel biomarker for lymph node metastasis in nasopharyngeal carcinoma.

Qiuyuan Wen,Jiadi Luo,Lina Xu,Weiyuan Wang,Shuzhou Chu,Jiao Li,Donghai Huang,Lei She,Guiyuan Xie,Songqing Fan,Duo Li,Joseph S Pagano

doi:10.1371/journal.pone.0101676

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. Flotillin-2 (Flot-2) is not only an important component of cellular membrane, but also involves in various cellular processes such as membrane trafficking, T cell and B cell activation, regulation of several signaling pathways associated with cell growth and malignant transformation, keeping structure and junction of epidermal cells and formation of filopodia. Although such molecular effects of Flot-2 have been reported, whether the expression of Flot-2 protein is associated with clinicopathologic implication for NPC has not been reported. The purpose of this research is to investigate the expression of Flot-2 protein in NPC and control nasopharyngeal epithelial tissues by immunohistochemistry and elucidate the association between the expression of Flot-2 protein and clinicopathological characteristics of NPC. The results showed that the positive percentage of Flot-2 expression in the NPC, nasopharyngeal epithelia with atypical hyperplasia and in the control nasopharyngeal mucosa epithelia was 88.8% (119/134), 76.9% (10/13) and 5.7% (5/88), respectively. There was significantly higher expression of Flot-2 protein in NPC and nasopharyngeal epithelia with atypical hyperplasia compared to the control nasopharyngeal mucosa epithelia (P<0.001, respectively). The positive percentage of Flot-2 protein expression in NPC patients with lymph node metastasis was significantly higher than those without lymph node metastasis. Increasing of Flot-2 expression was obviously correlated with clinical stages of NPC patients. The expression of Flot-2 was proved to be the independent predicted factor for lymph node metastasis by multivariate analysis. The sensitivity of Flot-2 for predicting lymph node metastasis of NPC patients was 93%. Taken together, our results suggest that the increased expression of Flot-2 protein is a novel higher sensitivity biomarker that can predict lymph node metastases in NPC.

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, which is derived from nasopharyngeal epithelium with characteristics of early cervical lymph node metastasis and high incidence rate of distant metastasis
We examined the positive expression and cellular location of Flot-2 in NPC, atypical hyperplasia nasopharyngeal epithelial specimens and control of normal nasopharyngeal epithelial tissues by IHC
High positive expression of Flot-2 protein (Fig 1A) was identified on the NPC cell membranes and weak Flot-2 membrane-staining was found in the atypical hyperplasia nasopharyngeal epithelial cells (Fig 1B)

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, which is derived from nasopharyngeal epithelium with characteristics of early cervical lymph node metastasis and high incidence rate of distant metastasis. Flotillin-2 (Flot-2) is a highly conserved protein and belongs to the SPFH (Stomatin/Prohibitin/Flotillin/HflK/C) protein superfamily, which is initially identified as a protein that is up-regulated during axon regeneration after optic nerve lesion [4,5]. It is a major protein from caveolae/lipid raft and is involved in epidermal cell adhesion and plays an important role in inducing the formation of filopodia [5]. Over-expression of Flot-2 has been reported to be associated with human melanoma progression and lymph node metastasis [6,7]. Whether the alteration of the expression of Flot-2 protein is associated with development and progression or clinicopathologic/prognostic implication for NPC has not been reported. We have investigated the expression of Flot-2 protein in 134 cases of NPC, 13 cases of nasopharyngeal epithelial specimens with atypical hyperplasia and 88 cases of control nasopharyngeal epithelial specimens by Immunohisto-

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