P53 overexpression and Epstein‐Barr virus infection in undifferentiated and squamous cell nasopharyngeal carcinomas

Abstract

We have analysed 22 nasopharyngeal carcinomas (NPCs) for expression of the small nuclear Epstein-Barr virus (EBV)-encoded RNAs (EBERs) and for immunohistologically detectable overexpression of p53. In situ hybridization demonstrated expression of the EBERs in 13 undifferentiated NPCs while nine squamous cell NPCs were EBER-negative. These results therefore confirm our previous DNA-DNA in situ hybridization studies and demonstrate that in the nasopharynx EBV is exclusively associated with undifferentiated but not with squamous cell carcinomas. p53 overexpression was demonstrated by immunohistology in 5 of 9 squamous cell NPCs and in 9 of 13 undifferentiated NPCs. Thus, there appears to be no correlation of p53 overexpression with EBV infection. These results are unexpected in the light of previous studies demonstrating that the p53 gene in primary undifferentiated NPC is consistently in the wild-type configuration. By contrast, analyses of squamous cell carcinomas of the head and neck have demonstrated that p53 overexpression in these cases is the result of p53 gene mutation. Whilst more detailed genetic analysis is required, our results suggest that mechanisms other than mutation of the p53 gene may be responsible for the stabilization of the protein in cases of undifferentiated NPC. It is tempting to speculate that an EBV-encoded protein may be involved.

High level expression of ΔN-p63: a mechanism for the inactivation of p53 in undifferentiated nasopharyngeal carcinoma (NPC)?

“…Immunohistochemistry for p53 expression showed that many of the malignant epithelial cells in the tumours expressed readily detectable levels of nuclear p53 (summarized in Table 2). Again this was consistent with previous reports (Niedobitek et al, 1993;Sheu et al, 1995;Murono et al, 1999).…”

“…Characteristically these undi erentiated tumours include a signi®cant in®ltration of T lymphocytes (reviewed in Niedobitek et al, 1996), up to 60% fail to express the tumour suppressor protein p16 INK4A (Lo et al, 1995(Lo et al, , 1996Sun et al, 1995;Gulley et al, 1998) and ± unlike most human tumours ± nearly 100% are wild type for the p53 tumour suppressor gene (E ert et al, 1992;Sun et al, 1992;Lo et al, 1992;Spruck et al, 1992). Paradoxically and in contrast to most normal tissues, although only wild type p53 alleles are present, in most NPC su cient p53 is expressed for it to be detectable by immunohistochemistry (Niedobitek et al, 1993;Sheu et al, 1995;Murono et al, 1999). Since these cells are rapidly proliferating, the p53 protein is assumed to be inactivated.…”

LMP1 signaling and activation of NF-κB in LMP1 transgenic mice

“…LMP1 has also been suggested to induce p53 expression in resting human B cells through NF-kB induction, resulting in the accumulation of p53 protein and elevated levels of p53 detected in NPC (Niedobitek et al, 1993;Chen and Cooper, 1996). To detect effects of LMP1 expression on p53 protein levels, immunoblot analysis for p53 in whole-cell extracts from lymphomas in transgenic and control mice revealed consistently high levels of p53 in all LMP1 transgenic lymphomas (L1-5), while spontaneous LMP1-negative counterparts demonstrated lower and variable levels of p53 (C1-3) (Figure 6b).…”

Epstein-Barr virus latent membrane protein does not inhibit differentiation and induces tumorigenicity of human epithelial cells

“…This model system can also be used to evaluate the contribution of host cell genetic factors, such as tumour suppressor genes and activated cellular oncogenes, to the formation of tumours in SCID mice. We analysed expression of the p53 tumour suppressor gene and the anti-apoptotic bcl-2 gene in tumours produced by HaCaT LMP transfectants as overexpression of both genes has been implicated in the pathogenesis of NPC (Niedobitek et al, 1993;Lu et al, 1993). Tumour sections were negative for bcl-2, indicating that bcl-2 does not play a role in tumour development.…”

“…Mutation and/or overexpression of the p53 tumour suppressor gene is a frequent event in many types of human cancer (Hollstein et al, 1991) including NPC (Niedobitek et al, 1993). Mutation resulting in overexpression of the HaCaT p53 gene has been reported (Lehman et al, 1993), and raises the possibility that this property of the HaCaT cell line is required to allow expression of LMP oncogenicity.…”