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Cell-cycle regulators, bcl-2 and NF-κB in Epstein-Barr virus-positive gastric carcinomas.pdf

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Cell-cycle regulators, bcl-2 and NF-κB in Epstein-Barr virus-positive gastric carcinomas

INTERNATIONAL JOURNAL OF ONCOLOGY 27: 1265-1272, 2005 Cell-cycle regulators, bcl-2 and NF-KB in Epstein-Barr virus-positive gastric carcinomas MEESOO CHANG14, HYE SEUNG LEE2, EUNJIJUNG2, CHULWOOKIM1, BYUNGLANLEE3 and WOO HO KIM1-2 Department of Pathology, Cancer Research Institute, Department of Anatomy, Seoul National University College of Medicine, 28 Yongon-dong, Seoul 110-799; 4Department of Pathology, Seoul National University Boramae Hospital, 425 shindaebang-dong, Seoul 156-707, Korea Received June 6,2005; Accepted July 14,2005 Abstract. The mechanism by which Epstein-Barr virus (EBV) contributes to the carcinogenesis of gastric mucosa remains unanswered. In this study, the role of cell-cycle regulators (p53, p21, p27, pl6, cyclin Dl , Rb), bcl-2 and NF-KB p65 (Rel A) was evaluated. Immunohistochemistry for these proteins was performed in EBV-positive (n=55) and EBV- negative gastric carcinomas (n=72). The bcl-2 protein by Western blot and EBV transcripts using RT-PCR were studied in cell lines. The p27 loss, pi6 loss, cyclin Dl expression and NF-KB nuclear positivity were more frequent in EBV-positive gastric carcinomas than those in EBV-negative gastric carcinomas, while p53 overexpression seldom occurred in EBV-positive carcinomas (p0.001). EBV-positive gastric carcinoma showed unique p53 immunostaining (hetero- geneous, weak to moderate, focal staining), and rare bcl-2 positivity (1 case). Western blot showed bcl-2 to be irrespective of EBV status in stomach cancer cell lines. However, bcl-2 was highly expressed in EBV-positive lymphoma or EBV- positive lymphoblastoid cell lines. The BARF1 transcript was confirmed in both EBV-positive stomach cancer and EBV-positive lymphoma, suggesting tissue type-specific bcl-2 activation by BARF1. The pathological tumor stage was the only independent prognostic factor. A small size of tumor, pi6 preservation and NF-KB nuclear positivity were associated with a good prognosis in univariate a