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Purpose: EBV has been detected in 2-16% of gastric carcinomas. However, there is little information available about the gene expression profile of EBV-positive gastric carcinomas.Experimental Design: EBV infection was examined using EBV-encoded small RNAs (EBERs) in situ hybridization, and 63 (5.6%) of 1127 consecutive gastric carcinomas were found to be EBV-positive. The expressions of 27 tumorassociated proteins were evaluated immunohistochemically in 63 EBV-positive gastric carcinomas and 287 EBV-negative carcinomas using the tissue array method. In addition, the genotype of EBV was investigated by PCR amplification of LMP1 (latent membrane protein 1), Epstein-Barr nuclear antigen 2 (EBNA2), and EBNA3B genes.Results: EBV-positive gastric carcinomas are characterized by the presence of lymphoid stroma, proximal location, and predominance in males. In comparison with EBVnegative carcinomas, EBV-positive carcinomas showed frequent loss of expression of p16, smad4, FHIT, and KAI-1 (kangai 1; P < 0.05), but retained the expression of APC (adenomatous polyposis coli), DCC (deleted in colorectal cancer), and some DNA repair proteins (P < 0.05). There was negative association between EBV infection and the expression of MUC1, MUC2, MUC5AC, p53, CEA, C-erbB2, and smad7. Using hierarchical cluster analysis, we divided EBV-positive gastric carcinomas into two clusters. Those patients with cluster 1 (42 cases) carcinomas had a better prognosis than those with cluster 2 (12 cases; P ‫؍‬ 0.0002) or those with EBV-negative carcinomas (280 cases;

Background:The underlying mechanisms involved in the activation of hypoxia-inducible factor-1 (HIF-1) in gastric cancer remain unclear. As nuclear factor-κB (NF-κB) as well as HIF-1 have been implicated in angiogenesis of various cancers, we investigated their relationship in gastric cancer.Methods:Nuclear expressions of HIF-1α and NF-κB/RelA were assessed in 251 human gastric carcinoma specimens by immunohistochemical tissue array analysis. Stable human gastric cancer cells, infected with a retroviral vector containing super-suppressive mutant form of IκBα (IκBαM), were used for animal studies as well as cell culture experiments. Xenografted tumours were measured and IκBαM effects on angiogenesis and HIF-1α activation were assessed by immunohistochemistry, western blotting, luciferase reporter assay, and semiquantitative reverse transcription–polymerase chain reaction. In addition, NF-κB effects on the HIF-1α degradation and synthesis were examined.Results:Hypoxia-inducible factor-1α activation positively correlated with RelA activation in clinical gastric cancer samples (P<0.001). The IκBαM overexpression suppressed tumour growth, microvessel density, and HIF-1α activation in xenografted tumours. Cell culture experiments showed that hypoxia-induced HIF-1α expression was reduced by NF-κB inhibition under hypoxic conditions at the translational level.Conclusion:The hypoxia-dependent activation of the NF-κB/HIF-1α/VEGF pathway contributes, at least in part, to gastric cancer promotion via enhancement of angiogenesis.