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Macrophage Inflammatory Protein-3 Is a Novel Serum Marker for Nasopharyngeal Carcinoma Detection and Prediction of Treatment Outcomes

Authors' Affiliations: Departments of ¹ Otolaryngology-Head and Neck Surgery, ² Radiation Oncology, ³ Genomic Medicine Research Core Laboratory, ⁴ Internal Medicine, Division of Hematology-Oncology, and ⁵ Pathology, Chang Gung Memorial Hospital at Lin-Kou; ⁶ Molecular Medicine Research Center; ⁷ Graduate Institute of Clinical Medical Sciences; and ⁸ Department of Cell and Molecular Biology, Chang Gung University, Taiwan

Requests for reprints: Jau-Song Yu, Department of Cell and Molecular Biology, Chang Gung University, No. 259 Wen-Hwa 1st Road, Kwei-Shan, Taoyuan, Taiwan. Phone: 886-3-2118800, ext. 5171; Fax: 886-3-2118891; E-mail: yusong{at}mail.cgu.edu.tw.

Purpose: We herein examine whether macrophage inflammatory protein-3 (MIP-3) is a biomarker for nasopharyngeal carcinoma (NPC) and whether it is involved in modulating NPC cell functions.

Experimental Design: The study population comprises 275 NPC patients and 250 controls. MIP-3 levels in tissues and sera were examined by immunohistochemistry and ELISA, respectively. EBV DNA load and EBV viral capsid antigen IgA were measured by quantitative real-time PCR and immunofluorescence assay, respectively. Effects of MIP-3 on NPC cell motility were investigated by Transwell migration/invasion assays and RNA interference.

Results: MIP-3 was overexpressed in NPC tumor cells. Serum MIP-3 levels were significantly higher in untreated patients, recurrent patients and patients with distant metastases versus non-NPC controls, patients with complete remission, and long-term disease-free patients. In the prospective cohort, serum MIP-3 levels were significantly higher in untreated NPC patients with advanced tumor-node-metastasis stage versus early stage and also correlated with EBV DNA load. Measurement of MIP-3, EBV DNA, and viral capsid antigen IgA levels in serial serum/plasma samples from treated patients at 6-month intervals revealed a high association between MIP-3 level, EBV DNA load, and disease status. Among 155 consecutive NPC patients, subjects with pretreated MIP-3 serum levels over 65 pg/mL had worse prognoses for overall survival and distant metastasis-free survival in univariate and multivariate analysis. Additionally, cell functional assays showed that MIP-3 contributed to migration and invasion of NPC cells, which could be effectively inhibited by MIP-3 knockdown.

Conclusions: MIP-3 may be a novel biomarker and prognosticator for NPC and is involved in migration and invasion of NPC cells.