Cyclin D1 overexpression supports stable EBV infection in nasopharyngeal epithelial cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 50; pp. E3473 - E3482
• Main Authors: Tsang, Chi Man, Yip, Yim Ling, Lo, Kwok Wai, Deng, Wen, To, Ka Fai, Hau, Pok Man, Lau, Victoria Ming Yi, Takada, Kenzo, Lui, Vivian Wai Yan, Lung, Maria Li, Chen, Honglin, Zeng, Musheng, Middeldorp, Jaap Michiel, Cheung, Annie Lai-Man, Tsao, Sai Wah
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 11-12-2012; National Acad Sciences
• Series: PNAS Plus
• Subjects: Base Sequence; Biological Sciences; carcinoma; Cell Cycle; Cell Differentiation; Cell growth; Cell Line, Tumor; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellular Senescence; Cyclin D1 - genetics; Cyclin D1 - metabolism; cyclins; DNA, Viral - genetics; epithelial cells; Epithelial Cells - metabolism; Epithelial Cells - pathology; Epithelial Cells - virology; epithelium; Epstein-Barr Virus Infections - complications; Epstein-Barr Virus Infections - genetics; Epstein-Barr Virus Infections - metabolism; Epstein-Barr Virus Infections - virology; Gene Expression; Genes, bcl-1; Genes, Viral; Herpesvirus 4, Human - genetics; Herpesvirus 4, Human - pathogenicity; Humans; Nasopharyngeal Neoplasms - etiology; Nasopharyngeal Neoplasms - genetics; Nasopharyngeal Neoplasms - metabolism; Nasopharyngeal Neoplasms - pathology; Nasopharynx - metabolism; Nasopharynx - pathology; Nasopharynx - virology; Pathogenesis; PNAS Plus; Precancerous Conditions - etiology; Precancerous Conditions - genetics; Precancerous Conditions - metabolism; Precancerous Conditions - pathology; Signal Transduction; Telomerase; Telomerase - genetics; Telomerase - metabolism; Tumors; Viral infections
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1202637109

Undifferentiated nasopharyngeal carcinomas (NPCs) are commonly present with latent EBV infection. However, events regulating EBV infection at early stages of the disease and the role of EBV in disease pathogenesis are largely undefined. Genetic alterations leading to activation of cyclin D1 signaling in premalignant nasopharyngeal epithelial (NPE) cells have been postulated to predispose cells to EBV infection. We previously reported that loss of p16, a negative regulator of cyclin D1 signaling, is a frequent feature of NPC tumors. Here, we report that early premalignant lesions of nasopharyngeal epithelium overexpress cyclin D1. Furthermore, overexpression of cyclin D1 is closely associated with EBV infection. Therefore we investigated the potential role of cyclin D1 overexpression in dysplastic NPE cells in vitro. In human telomerase reverse transcriptase-immortalized NPE cells, overexpression of cyclin D1 or a p16-resistant form of CDK4 (CDK4 ᴿ²⁴C) suppressed differentiation. This suppression may have implications for the close association of EBV infection with undifferentiated NPC. In these in vitro models, we found that cellular growth arrest and senescence occurred in EBV-infected cell populations immediately after infection. Nevertheless, overexpression of cyclin D1 or a p16-resistant form of CDK4 or knockdown of p16 in the human telomerase reverse transcriptase-immortalized NPE cell lines could counteract the EBV-induced growth arrest and senescence. We conclude that dysregulated expression of cyclin D1 in NPE cells may contribute to NPC pathogenesis by enabling persistent infection of EBV.