Lack of cytotoxic property in a variant of Epstein–Barr virus latent membrane protein-1 isolated from nasopharyngeal carcinoma (original) (raw)
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Journal of Virology, 2015
can modulate oncogenic and cell death mechanisms. The viral latent membrane proteins 1 (LMP1) and LMP2A are consistently expressed in NPC and can cooperate in bitransgenic mice expressed from the keratin-14 promoter to enhance carcinoma development in an epithelial chemical carcinogenesis model. In this study, LMP1 and LMP2A were coexpressed in the EBV-negative NPC cell line HK1 and examined for combined effects in response to genotoxic treatments. In response to DNA damage activation, LMP1 and LMP2A coexpression reduced ␥H2AX (S139) phosphorylation and caspase cleavage induced by a lower dose (5 M) of the topoisomerase II inhibitor etoposide. Regulation of ␥H2AX occurred before the onset of caspase activation without modulation of other DNA damage signaling mediators, including ATM, Chk1, or Chk2, and additionally was suppressed by inducers of DNA single-strand breaks (SSBs) and replication stress. Despite reduced DNA damage repair signaling, LMP1-2A coexpressing cells recovered from cytotoxic doses of etoposide; however, LMP1 expression was sufficient for this effect. LMP1 and LMP2A coexpression did not enhance cell growth, with a moderate increase of cell motility to fibronectin. This study supports that LMP1 and LMP2A jointly regulate DNA repair signaling and cell death activation with no further enhancement in the growth properties of neoplastic cells.
NF-κB is required for cell death induction by latent membrane protein 1 of Epstein–Barr virus
Cellular Signalling, 2003
NF-nB is a transcription factor known to promote or antagonize cell death depending on cell types and stimuli. Here, we demonstrate that expression of latent membrane protein 1 (LMP1), an Epstein-Barr virus (EBV)-encoded membrane protein, triggers programmed cell death in an NF-nB-dependent manner. Co-expression of NF-nB inhibitors completely prevented activation of NF-nB and LMP1-induced cell death. Addition therein of RelA, an active subunit of NF-nB, restored the NF-nB activation and cell death induction by LMP1, but RelA alone did not induce cell death. These results indicate that the activation of NF-nB is required for cell death induced by LMP1. Moreover, LMP1 induced activation of caspase-3 via the activation of NF-nB. Studies with z-VAD-fmk, a caspase inhibitor, indicated that NF-nB mediated both caspase-dependent and-independent death pathways. In conclusion, the cell death induced by LMP1 uncovered caspasedependent and-independent death pathways both of which require NF-nB.
Epstein-Barr Virus Latent Membrane Protein-1 Expression in Nasopharyngeal Carcinoma
JCO Global Oncology
PURPOSE Nasopharyngeal carcinoma (NPC), a malignant neoplasm of the epithelium covering the nasopharynx, is a rare disease in most parts of the world. Epstein-Barr virus (EBV), the most potent oncogenic virus, coupled with environmental and genetic factors has been identified to play a role in the development of NPC. An array of methods for detecting the virus do exist, from serologic detection of antibodies to DNA amplification. There is paucity of local data on the status of EBV infection in relation to NPC within the region, and this study attempts to shed more light on the subject. METHODS This was a retrospective cross-sectional laboratory-based study on histologically confirmed, archived tissues from July 2015 to June 2019. Immunohistochemistry expression of latent membrane protein-1 (LMP-1) was used to detect EBV infection in the tissues. RESULTS A total of 71 cases were enrolled in this study. The mean age was 47.87 years ± 16.84 years with a male-to-female ratio of 1.5:1. T...
Journal of General Virology, 1995
The presence of transcripts of the Epstein-Barr virus genes for Epstein-Barr nuclear antigen (EBNA)-I and EBNA-2 and for latent membrane protein (LMP)-I, LMP-2A and LMP-2B was investigated in 24 nasopharyngeal carcinoma (NPC) biopsies of Chinese origin and two NPC-derived solid tumour lines, CAO and C15, of Chinese and north African origin respectively, propagated by serial transplantation in nude mice. Transcripts were detected by PCR amplification of cDNA. EBNA-1 transcripts were present in all biopsies tested and originated exclusively from the FQ promoter while the C and W promoters were inactive. Using nested primers, LMP-1 and LMP-2B RNAs were found to be co-ordinately expressed in 22 of the 24 biopsies, while the two remaining tumours were negative for both. LMP-2A transcription was detected in 17 of the 22 LMP-l-positive biopsies. In summary, the following patterns of viral gene expression were observed in the tumour biopsies: (i) LMP-1-LMP-2B and LMP-2A positive (17 biopsies); (ii) LMP-1-LMP-2B positive but LMP-2A negative (five biopsies); (iii) no viral gene other than EBNA-1 expressed (two biopsies).
European Journal of Cancer Part B: Oral Oncology, 1996
Nasopharyngeal carcinoma (NIX) paraffin samples, from Spanish patients, of distinct histological types, including squamous cell carcinoma (10 cases), nonkeratinising carcinoma (12 cases) and undifferentiated carcinoma (29 cases) were analysed for Epstein-Barr virus (EBV) detection and EBV-encoded latent membrane protein (LIMP-l) expression using a sensitive nested-polymerase chain reaction with four oligonucleotide primers specific for EBV genome (EB-1, 2, 3, 4) and immunohistochemistry by means of CS1-4 pool monoclonal antibody. EBV genome was detected regardless of histological type in lOOo/o of samples with sufficient DNA quality to permit viral diagnosis (50 out of 51 cases), supporting the previous view that all types of NPC are variants of an EBVassociated malignancy. However LMP-1, an EBV-encoded oncogenic protein, was detected in 40 out of 51 samples (78.4%) and LIMP-1 immunohistochemical expression was not apparently influenced by histological type, primary or metastatic site, clinical stage, age or sex. This high percentage of detection of LIMP-1 in our cases supports a role for EBV in the pathogenesis of different types of NIX, but the lack of constant expression of LMP-1 in NIX remains unclear and various reasons are postulated to explain the absence of this oncogenic protein in some EBV-associated NPCs. Copyright 0 1996 Elsevier Science Ltd
International Journal of Cancer, 2004
EBV infection is associated with virtually all cases of undifferentiated NPC, and the EBV-encoded LMP1 is expressed in a proportion of cases. LMP1 has transforming functions similar to members of the TNF receptor family and activates intracellular signaling cascades through interaction with TRAFs. In B cells, expression of TRAF1 is in turn upregulated by LMP1. LMP1 signaling in epithelial cells may be affected by the presence or absence of TRAF1. By immunohistochemistry, we detected TRAF1 expression in 17 of 42 (40%) EBV ؉ undifferentiated NPCs. All 7 LMP1 ؉ NPC biopsies were also TRAF1 ؉ . Using an RNAse protection assay, high-level TRAF1 expression was detected in an LMP1-expressing NPC-derived cell line (C15) and expression was weaker in 2 LMP1cell lines (C17, C19). Finally, LMP1 upregulated TRAF1 expression in an EBVkeratinocyte cell line. Our results demonstrate that TRAF1 is expressed in NPC tumor cells in vivo and suggest that TRAF1 expression may be upregulated by LMP1 in NPC. An antiapoptotic function has been proposed for TRAF1, and this may be relevant for the pathogenesis of NPC.
Journal of Virology, 2008
The Epstein-Barr virus (EBV) oncoprotein latent membrane protein 1 (LMP1) is thought to act as the major transforming protein in various cell types, by rerouting the tumor necrosis factor receptor family signaling pathway. Despite this implication in EBV-associated transformation of cells, LMP1 toxicity is a well-known but poorly studied feature, perhaps because it contradicts its role in transformation. We show that LMP1 physiological levels are very heterogeneous and that the highest levels of LMP1 correlate with Fas overexpression and spontaneous apoptosis in lymphoblastoid cell lines (LCLs). To understand the cytotoxic effect of LMP1 in LCLs, we cloned wild-type LMP1 into a doxycycline double-inducible episomal vector pRT-1, with a truncated version of NGFR as a surrogate marker of inducibility. We found that LMP1 overexpression induced apoptosis in LCL B cells, as shown by annexin V labeling, sub-G1 peak, and poly(ADP ribose) polymerase cleavage. Knocking down Fas expression by...
Epstein-Barr virus genes and nasopharyngeal cancer
2006
widespread in all areas of the world, infecting over 95% of the adult population. EBV primarily infects and replicates in the stratified squamous epithelium of the oropharynx during acute infection. Besides, its well-known tropism for B cells, the targets of EBV infection may also include epithelial cells, T cells, and cells of the macrocytic, granulocytic, and natural killer lineages. Although most humans coexist with the virus without serious sequelae, a small proportion will develop tumors. Almost every undifferentiated nasopharyngeal carcinoma (NPC) is EBV positive, despite geographical origin. EBV-derived IL-10 which is considered to play a role in the establishment of latent infection by suppression of the host immune system, may contribute to the growth of the tumor and to immune evasion. Latent membrane protein-1 (LMP-1) has transforming ability and support to the concept that EBV is involved in the pathogenesis of NPC. The association of NPC with EBV has been firmly established however the evidence indicating a role for the virus in the pathogenesis is still unknown and controversial. The main question is how the EBV-infected cells can escape from the immune response. [Turk J Cancer 2006;36(3):97-107].
Oncogene, 1997
Latent membrane protein (LMP) is a latent Epstein-Barr virus (EBV) protein expressed in the EBV associated malignancy, nasopharyngeal carcinoma (NPC). Properties ascribed to this protein include inhibition of epithelial cell dierentiation and deregulation of epithelial cellular gene expression, and are believed to contribute to the development of NPC. Studies to evaluate the oncogenic potential of LMP in epithelial cells have not been conclusive. We carried out studies to determine the tumorigenic activity of LMP in two human epithelial cell lines, SCC12F and HaCaT; while SCC12F LMP transfectants were non-tumorigenic in severe combined immunode®cient mice, HaCaT LMP transfectants were strongly oncogenic. The tumours produced were well dierentiated, keratinising squamous cell carcinomas suggesting that LMP does not inhibit epithelial cell dierentiation which con¯icts with a previous report by Dawson et al. (1990). To resolve this discrepancy we examined the ability of HaCaT and SCC12F LMP transfectants to dierentiate in a suspension culture assay. Both lines were able to dierentiate to a similar extent as parental lines and control transfectants. Our results indicate that LMP is strongly oncogenic in human epithelial cells but that inhibition of dierentiation is not necessarily a mechanism by which LMP contributes to the pathogenesis of NPC.
Seminars in Cancer Biology, 2012
Although frequently expressed in EBV-positive malignancies, the contribution of the oncogenic latent membrane proteins, LMP1 and LMP2, to the pathogenesis of nasopharyngeal carcinoma (NPC) is not fully defined. As a key effector in EBV-driven B cell transformation and an established "transforming" gene, LMP1 displays oncogenic properties in rodent fibroblasts and induces profound morphological and phenotypic effects in epithelial cells. LMP1 functions as a viral mimic of the TNFR family member, CD40, engaging a number of signalling pathways that induce morphological and phenotypic alterations in epithelial cells. Although LMP2A plays an essential role in maintaining viral latency in EBV infected B cells, its role in epithelial cells is less clear. Unlike LMP1, LMP2A does not display "classical" transforming functions in rodent fibroblasts but its ability to engage a number of potentially oncogenic cell signalling pathways suggests that LMP2A can also participate in EBV-induced epithelial cell growth transformation. Here we review the effects of LMP1 and LMP2 on various aspects of epithelial cell behaviour highlighting key aspects that may contribute to the pathogenesis of NPC.