Enhanced IL-6/IL-6R Signaling Promotes Growth and Malignant Properties in EBV-Infected Premalignant and Cancerous Nasopharyngeal Epithelial Cells

• Published in: PloS one Vol. 8; no. 5; p. e62284
• Main Authors: Zhang, Guitao, Tsang, Chi Man, Deng, Wen, Yip, Yim Ling, Lui, Vivian Wai-Yan, Wong, Sze Chuen Cesar, Cheung, Annie Lai-Man, Hau, Pok Man, Zeng, Musheng, Lung, Maria Li, Chen, Honglin, Lo, Kwok Wai, Takada, Kenzo, Tsao, Sai Wah
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.05.2013; Public Library of Science (PLoS)
• Subjects: Activation; Animals; Biology; Cancer; Care and treatment; Cell Line, Tumor; Cell Proliferation; Cytokines; Development and progression; Epithelial cells; Epithelial Cells - physiology; Epstein-Barr virus; Epstein-Barr Virus Infections - immunology; Epstein-Barr Virus Infections - metabolism; Etiology; Gene Expression; Gene Expression Regulation, Neoplastic; Health aspects; Herpesvirus 4, Human - immunology; Humans; Infections; Inflammation; Interleukin 6; Interleukin 6 receptors; Interleukin-6 - genetics; Interleukin-6 - metabolism; Interleukins; Invasiveness; Kinases; Laboratories; Male; Medical research; Medicine; Mice; Mice, Nude; Nasopharyngeal cancer; Nasopharyngeal carcinoma; Nasopharyngeal Neoplasms - metabolism; Nasopharyngeal Neoplasms - pathology; Nasopharyngeal Neoplasms - virology; Neoplasm Transplantation; Pathogenesis; Precancerous Conditions - metabolism; Precancerous Conditions - pathology; Precancerous Conditions - virology; Properties (attributes); Receptors, Interleukin-6 - metabolism; Rodents; Signal Transduction; Signaling; Stat3 protein; STAT3 Transcription Factor - metabolism; Stromal cells; Throat cancer; Transcription; Transformation; Tumor Burden; Tumorigenicity; Tumors; Up-Regulation; Viral Matrix Proteins - genetics; Viral Matrix Proteins - metabolism; Virology; Viruses; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0062284

Nasopharyngeal carcinoma (NPC) is etiologically associated with Epstein-Barr virus (EBV) infection. However, the exact role of EBV in NPC pathogenesis remains elusive. Activation of signal transducer and activator of transcription 3 (STAT3) is common in human cancers including NPC and plays an important role in the pathogenesis and progression of human cancers. Interleukin-6 (IL-6), a major inflammatory cytokine, is a potent activator of STAT3. In this study, we report that EBV-infected immortalized nasopharyngeal epithelial (NPE) cells often acquire an enhanced response to IL-6-induced STAT3 activation to promote their growth and invasive properties. Interestingly, this enhanced IL-6/STAT3 response was mediated by overexpression of IL-6 receptor (IL-6R). Furthermore, IL-6R overexpression enhanced IL-6-induced STAT3 activation in uninfected immortalized NPE cells in vitro, and promoted growth and tumorigenicity of EBV-positive NPC cell line (C666-1) in vivo. Moreover, it is shown for the first time that IL-6R was overexpressed in clinical specimens of NPC. IL-6 expression could also be strongly detected in the stromal cells of NPC and a higher circulating level of IL-6 was found in the sera of advance-staged NPC patients compared to the control subjects. Therefore, IL-6R overexpression, coupled with enhanced IL-6/STAT3 signaling may facilitate the malignant transformation of EBV-infected premalignant NPE cells into cancer cells, and enhance malignant properties of NPC cells.