Cyclin D1 overexpression supports stable EBV infection in nasopharyngeal epithelial cells
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 signalin...
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| Published in: | Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 50; pp. E3473 - E3482 |
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| Format: | Journal Article |
| Language: | English |
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United States
National Academy of Sciences
11-12-2012
National Acad Sciences |
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| Abstract | 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. |
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| AbstractList | 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. 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^sup 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. [PUBLICATION ABSTRACT] 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. The establishment of persistent EBV infection in premalignant NPE cells harboring genetic alterations has long been postulated to be an early and important event in the pathogenesis of NPC. As illustrated in Fig. P1 , our results provide evidence that preexisting genetic alterations in premalignant NPE cells, notably the overexpression of cyclin D1 and related molecular events, support latent EBV infection and facilitate NPC development. By overexpressing cyclin D1 and CDK4 R24C or knocking down p16 in our telomerase-immortalized cell systems, we observed that the inhibitory effects of EBV infection on the growth of NPE cells could be suppressed, resulting in multiple colonies of EBV-infected NPE cells. This result indicates that genetic alterations that impair growth inhibition may be crucial for supporting EBV infection. We also examined the effect of cyclin D1 on the regulation of representative latent and lytic EBV genes. Up-regulation of EBV latent genes (including EBNA1 and EBER1/2 ) and down-regulation of lytic EBV genes (including BZLF1 , BRLF1 , BMRF1 , and BGLF4 ) were observed in NPE cells that overexpressed cyclin D1. BZLF1 -expressing cells were lost rapidly upon serial passages, indicating that cells undergoing lytic infection might not facilitate the long-term persistence of EBV. We then investigated the ability of EBV to infect and propagate in NP550hTert and NP361hTert cells. We observed that the immortalization of NPE cells, per se, is not sufficient to support stable EBV propagation. EBV infection readily induced the arrest of growth in these telomerase-immortalized cell lines. Examination of these EBV-infected immortalized cells revealed the expression of senescence-associated β-galactosidase (a cell senescence marker) and the up-regulated expression of p16 and p21 (which are proteins that arrest the cell cycle). Because EBV infection is highly associated with poorly or undifferentiated NPC, we investigated whether overexpression of cyclin D1 or the activation of the cyclin D1/CDK4 pathway might contribute to the undifferentiated property of dysplastic NPE cells by using telomerase-immortalized NPE cell lines derived from primary NPE tissues. Cyclin D1 or CDK4 R24C (a p16-insensitive mutant of CDK4) was overexpressed in the telomerase-immortalized cell lines (NP550hTert and NP361hTert) and was found to resist serum-induced differentiation. This observation may have implications for the close association of EBV infection with undifferentiated and poorly differentiated NPC but not with differentiated NPC. We previously reported that overexpression of cyclin D1 is closely associated with NPC ( 5 ). The relationship between cyclin D1 expression and EBV infection in dysplastic nasopharyngeal epithelium is unknown. It is difficult to find dysplastic NPE tissues, because most patients with NPC present clinically with late stages of the disease. However, for this study, we were able to retrieve six cases from our archival pathological specimens of dysplastic nasopharyngeal biopsies. The overexpression of cyclin D1 was observed in all six of these cases, as was the coexisting expression of EBV-encoded RNA (EBER), which is a reliable indicator of EBV infection. This finding indicates that cyclin D1 overexpression and EBV infection are closely correlated in the early stage of NPC development. The EBV genome has been detected in almost all, if not all, undifferentiated nasopharyngeal carcinoma (NPC) cells ( 1 ). EBV infection has been postulated to be an important etiological factor for NPC development ( 2 ). Clonal EBV genomes are present in early preinvasive dysplastic lesions and carcinomas in situ in nasopharyngeal epithelium, indicating that EBV infection is an early event in NPC development ( 3 ). The establishment of persistent EBV infection in premalignant nasopharyngeal epithelial (NPE) cells may represent a crucial step in the pathogenesis of NPC. Interestingly, EBV readily infects and propagates in B cells but not in NPE cells. Furthermore, EBV episomes in infected NPC are lost rapidly during long-term propagation in culture. At present, events regulating the infection and propagation of EBV in NPE cells are largely unknown. We previously reported the presence of genetic alterations, including the allelic deletion of chromosome 9p (which includes the p16 locus), in low-grade dysplastic lesions and histologically normal nasopharyngeal epithelium from human individuals at a high risk of developing NPC ( 4 ). Furthermore, the overexpression of cyclin D1, a protein involved in the regulation of cell-cycle progression, is common in primary NPC biopsies (detected in 35 of 38 cases) ( 5 ). The common deletion of p16, a key protein involved in inhibiting the activity of cyclin D1/CDK4 complex, in premalignant and cancerous nasopharyngeal epithelium and the frequent overexpression of cyclin D1 in NPC indicate that the dysregulation of the cyclin D1 pathway has a significant impact on the maintenance and propagation of EBV in premalignant NPE cells. It has been postulated that these genetic alterations in premalignant NPE cells provide a permissive cellular environment that supports the clonal expansion and propagation of EBV. In this study, we observed that EBV infection of telomerase-immortalized NPE cells induced cell-cycle arrest and senescence. Overexpression of cyclin D1 could suppress these growth-inhibitory effects associated with EBV infection and allow long-term propagation of EBV in infected NPE cells. 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. 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. |
| Author | Deng, Wen Zeng, Musheng Lau, Victoria Ming Yi Middeldorp, Jaap Michiel Yip, Yim Ling Lung, Maria Li Tsao, Sai Wah Lo, Kwok Wai To, Ka Fai Hau, Pok Man Tsang, Chi Man Lui, Vivian Wai Yan Cheung, Annie Lai-Man Takada, Kenzo Chen, Honglin |
| Author_xml | – sequence: 1 fullname: Tsang, Chi Man – sequence: 2 fullname: Yip, Yim Ling – sequence: 3 fullname: Lo, Kwok Wai – sequence: 4 fullname: Deng, Wen – sequence: 5 fullname: To, Ka Fai – sequence: 6 fullname: Hau, Pok Man – sequence: 7 fullname: Lau, Victoria Ming Yi – sequence: 8 fullname: Takada, Kenzo – sequence: 9 fullname: Lui, Vivian Wai Yan – sequence: 10 fullname: Lung, Maria Li – sequence: 11 fullname: Chen, Honglin – sequence: 12 fullname: Zeng, Musheng – sequence: 13 fullname: Middeldorp, Jaap Michiel – sequence: 14 fullname: Cheung, Annie Lai-Man – sequence: 15 fullname: Tsao, Sai Wah |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/23161911$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Copyright | Copyright National Academy of Sciences Dec 11, 2012 |
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| DocumentTitleAlternate | Cyclin D1 supports EBV infection |
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| Notes | http://dx.doi.org/10.1073/pnas.1202637109 Edited by Elliott Kieff, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, and approved October 12, 2012 (received for review March 6, 2012) 1C.M.T. and Y.L.Y. contributed equally to this work. Author contributions: C.M.T., P.M.H., and S.W.T. designed research; C.M.T., Y.L.Y., K.W.L., W.D., and V.M.Y.L. performed research; K.F.T., K.T., M.Z., J.M.M., and A.L.-M.C. contributed new reagents/analytic tools; C.M.T., K.W.L., W.D., H.C., and S.W.T. analyzed data; and C.M.T., V.W.Y.L., M.L.L., and S.W.T. wrote the paper. |
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| Snippet | Undifferentiated nasopharyngeal carcinomas (NPCs) are commonly present with latent EBV infection. However, events regulating EBV infection at early stages of... |
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| SubjectTerms | 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 |
| Title | Cyclin D1 overexpression supports stable EBV infection in nasopharyngeal epithelial cells |
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