Cell-cycle regulators, bcl-2 and NF-kappaB in Epstein-Barr virus-positive gastric carcinomas.
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, p16, cyclin D1, Rb), bcl-2 and NF-kappaB 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, p16 loss, cyclin D1 expression and NF-kappaB 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 (p<0.001). EBV-positive gastric carcinoma showed unique p53 immunostaining (heterogeneous, 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, p16 preservation and NF-kappaB nuclear positivity were associated with a good prognosis in univariate analysis (p<0.05). p27, p16, cyclin D1 and NF-kappaB may be associated with oncogenesis in EBV-positive gastric carcinomas. EBV-positive gastric carcinomas showed infrequent p53 overexpression, wild-type p53 stabilization and rare bcl-2 involvement. The characteristic expression of proteins may relate to both EBV and tissue type.
Chang
Mee Soo
MS
Department of Pathology, Seoul National University College of Medicine, Seoul 110-799, Korea.
Lee
Hye Seung
HS
Jung
Eun Ji
EJ
Kim
Chul Woo
CW
Lee
Byung Lan
BL
Kim
Woo Ho
WH
D000293:Adolescent; D000328:Adult; D000368:Aged; D015153:Blotting, Western; D002277:Carcinoma / Q000503:physiopathology / Q000821:virology*; D002453:Cell Cycle / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D019938:Cyclin D1 / Q000502:physiology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology; D020031:Epstein-Barr Virus Infections / Q000150:complications*; D005260:Female; D020869:Gene Expression Profiling; D004854:Herpesvirus 4, Human / Q000472:pathogenicity; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000096:biosynthesis / Q000502:physiology*; D009367:Neoplasm Staging; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000503:physiopathology / Q000821:virology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D015854:Up-Regulation
D019941:Cyclin-Dependent Kinase Inhibitor p16; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1