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Role of p53, apoptosis, and cell proliferation in early stage Epstein-Barr virus positive and negative gastric carcinomas

¹ Department of Pathology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
² Department of Molecular and Cellular Pathology, School of Medicine, University of Queensland, Herston, Brisbane, 4006, Australia
³ Third Department of Surgery, Tokyo Medical University

Correspondence to:
Dr H Ishii
Department of Pathology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan; hhishii{at}tokyo-med.ac.jp Aims: Mechanisms of Epstein-Barr virus (EBV) associated gastric tumour development are incompletely understood. The interrelations between EBV infection, apoptosis, cell proliferation, and the expression of the tumour suppressor gene p53 was investigated in 133 early stage gastric carcinomas.

Methods: Tumour tissue was compared with paired non-tumour tissue. EBV encoded small RNAs (EBERs) determined EBV status. The apoptotic index (AI) was determined by morphology and verified biochemically. p53 and Ki-67 expression (cell proliferation) was assessed using immunohistochemistry.

Results: EBV was detected in 14.3% of the cases. Cell proliferation did not differ significantly between EBV positive and negative cancers. However, within both these groups, the p53 positive and negative subsets differed significantly (EBV positive group: 76.8% and 55.3% were p53 positive or negative cancers, respectively; p<0.05; EBV negative group: 65.2% and 51.7% were p53 positive or negative, respectively; p<0.005). The numbers of p53 expressing EBV positive and negative cases were significantly different (57.9% and 82.5%, respectively; p<0.05). Compared with cell proliferation, apoptosis was significantly lower in EBV positive versus negative cancers (AI of 4.36 and 6.50, respectively; p<0.01). The p53 positive and negative subsets also differed significantly in AI (EBV positive group: AI of 5.13 and 3.30 for p53 positive and negative cancers, respectively; p<0.05: EBV negative group: AI of 6.84 and 4.90 for p53 positive and negative cancers, respectively; p<0.05).

Conclusions: These factors probably combine to promote development and progression of early stage gastric carcinomas and, at the same time, ensure the survival of EBV itself.

Abbreviations: AI, apoptotic index; BCIP–NBT, 5-bromo-4-chloro- 3-indolyl-phosphate/nitroblue tetrazolium; EBER, Epstein-Barr virus encoded small RNA; EBV, Epstein-Barr virus; ISH, in situ hybridisation; PBS, phosphate buffered saline; PCR-SSCP, polymerase chain reaction single stranded conformational polymorphism; PNA, peptide nucleic acid; TBS, Tris buffered saline; TUNEL, terminal deoxyribonucleotidyl transferase mediated dUTP–digoxigenin nick end labelling

Keywords: gastric carcinoma; Epstein-Barr virus; apoptosis; p53; proliferation; Ki-67