Low rate of apoptosis and overexpression of bcl‐2 in Epstein–Barr virus‐associated gastric carcinoma

Kume, Tohru; Oshima, Koichi; Shinohara, Tetsuo; Takeo, Hiroshi; Yamashita, Yuichi; Shirakusa, Takayuki; Kikuchi, Motoshi

doi:10.1111/j.1365-2559.1999.00686.x

Cited by 47 publications

(36 citation statements)

References 38 publications

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“…The loss of p16 protein is commonly associated with epigenetic mechanisms and is more common in EBV-infected tumors arising in the body of the stomach (24,25). In EBV-positive gastric carcinomas, bcl-2 expression was found to be significantly higher than that in EBV-negative carcinomas, whereas no significant difference in bcl-x expression was observed (26). By means of an analysis with 27 commercially available antibodies, we showed that EBV-positive carcinomas had a distinct expression profile in comparison with EBV-negative carcinomas.…”

Section: Discussionmentioning

confidence: 74%

Epstein-Barr Virus-Positive Gastric Carcinoma Has a Distinct Protein Expression Profile in Comparison with Epstein-Barr Virus-Negative Carcinoma

Lee¹,

Chang²,

Yang

et al. 2004

Clinical Cancer Research

113

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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;

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Section: Discussionmentioning

confidence: 74%

Epstein-Barr Virus-Positive Gastric Carcinoma Has a Distinct Protein Expression Profile in Comparison with Epstein-Barr Virus-Negative Carcinoma

Lee¹,

Chang²,

Yang

et al. 2004

Clinical Cancer Research

113

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“…Serum deprivation, mimicking the microenvironment of cancer tissue in vivo, is a strong inducer of apoptosis through the intrinsic pathway. Interestingly, a lower rate of apoptosis has also been well documented in EBV-associated gastric carcinoma in vivo (25); therefore, the mechanisms of resistance to apoptosis may be important in this type of gastric carcinoma and should be further investigated in relation to EBV infection.…”

Section: Discussionmentioning

confidence: 99%

Survival Advantage of EBV-Associated Gastric Carcinoma: Survivin Up-regulation by Viral Latent Membrane Protein 2A

Hino

Uozaki²,

Inoue³

et al. 2008

Cancer Research

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EBV-associated gastric carcinoma is a distinct subset of gastric carcinoma infected with EBV, which shows latency I type expression of EBV latent genes (EBNA1, EBER, BARF0, and LMP2A). To clarify the role of EBV in this type of gastric carcinoma, the cell biological characteristics (growth, apoptosis, and migration) were evaluated in gastric carcinoma cell lines (MKN-1, TMK1, MKN-74 and MKN-7) with and without infection of recombinant EBV harboring the neomycin resistance gene. The infection reiterated the latency I type infection, and the only difference observed in EBV-infected gastric carcinoma cell lines was the resistance to serum deprivation-induced apoptosis. Comparative analyses of transcripts of apoptosis-associated genes in MKN-1 and EBV-MKN-1 and subsequent quantitative reverse transcription-PCR analysis showed up-regulation of the cellular survivin gene in EBV-infected gastric carcinoma cell lines. Small interfering RNA-mediated knockdown of survivin increased apoptosis in EBV-MKN-1 to the level of the original MKN-1 cells. Transfection of EBV-latent genes into MKN-1 showed that LMP2A, but not EBNA1, EBER, or BARF0, up-regulated survivin gene expression. LMP2A-mediated survivin up-regulation in gastric carcinoma cells was inhibited with a nuclear factor-KB (NF-KB) inhibitor, Bay 11-7082. In parallel with these findings in vitro, survivin expression was frequent in carcinoma tissues of gastric carcinoma by immunohistochemistry, and significantly more in EBV-associated gastric carcinoma (12 of 13) than in EBV-negative gastric carcinoma in the advanced stage (P = 0.0307). Thus, EBV uses its latent protein, LMP2A, to activate the NF-KB-survivin pathway to rescue EBV-infected epithelial cells from serum deprivation, and up-regulation of survivin may play a role in the progression of this specific type of gastric carcinoma infected with EBV.

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“…Kume et al [12] reported that EBV-positive gastric adenocarcinomas had bcl -2 overexpression and a low rate of apoptosis. They also mentioned that a low apoptotic index was seen in EBV-positive GCLRS which was related to a good prognosis although the exact mechanism has not yet been elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…Kume et al [12] reported the expression of bcl-2 in EBV-positive gastric carcinoma and low apoptosis, suggesting a relationship between EBV and apoptosis. Unlike necrosis, apoptosis is active and programmed cell death and many studies have been conducted on apoptosis in carcinogenesis.…”

mentioning

confidence: 99%

Relationship between Epstein-Barr Virus-Encoded RNA Expression, Apoptosis and Lymphocytic Infiltration in Gastric Carcinoma with Lymphoid-Rich Stroma

Cho

Kim

et al. 2004

Med Princ Pract

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Objective: To investigate the association of apoptosis with apoptotic proteins and Epstein-Barr virus (EBV) expression in gastric carcinoma with lymphoid-rich stroma (GCLRS) in order to clarify the relationship between lymphocytic infiltration, EBV expression and apoptosis in gastric carcinoma. Subjects and Methods: We performed immunohistochemical stains for bcl-2, bax and in situ hybridization for EBV-encoded RNA and the terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling technique using the 24 cases of GCLRS and 23 cases of gastric carcinoma with lymphoid-poor stroma (GCLPS) out of 1,635 cases of gastric carcinoma. Results: The prevalence of GCLRS was 1.47% (24/1,635). The prevalence of EBV involvement in GCLRS (79%, 19/24) was significantly higher than in GCLPS (8.7%, 2/23). Apoptosis was revealed in all cases and there was no statistical difference between GCLRS and GCLPS. Immunohistochemical expression for bcl-2 was revealed only in the cytoplasm of lymphocytes in all cases, but bax showed distinct expression in the cytoplasm of neoplastic cells in all cases. There was a significant correlation between bax expression and the apoptotic index (p < 0.05). Lymphocytic infiltration was significantly correlated with the expression of EBV (p < 0.05) but not with survival rate and apoptosis. Most of the GCLRS cases were rated as low clinical stage (stage IA or B) and seemed to have a good prognosis. Conclusions: These results support the hypothesis that EBV infection plays an important role in the tumorigenesis of GCLRS, which has a better prognosis than usual gastric adenocarcinoma although there was no significant difference in the apoptotic index between GCLRS and GCLPS.

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Low rate of apoptosis and overexpression of bcl‐2 in Epstein–Barr virus‐associated gastric carcinoma

Cited by 47 publications

References 38 publications

Epstein-Barr Virus-Positive Gastric Carcinoma Has a Distinct Protein Expression Profile in Comparison with Epstein-Barr Virus-Negative Carcinoma

Epstein-Barr Virus-Positive Gastric Carcinoma Has a Distinct Protein Expression Profile in Comparison with Epstein-Barr Virus-Negative Carcinoma

Survival Advantage of EBV-Associated Gastric Carcinoma: Survivin Up-regulation by Viral Latent Membrane Protein 2A

Relationship between Epstein-Barr Virus-Encoded RNA Expression, Apoptosis and Lymphocytic Infiltration in Gastric Carcinoma with Lymphoid-Rich Stroma

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