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

Hino, Rumi; Uozaki, Hiroshi; Inoue, Yoko; Shintani, Yoshizumi; Ushiku, Tetsuo; Sakatani, Takashi; Takada, Kenzo; Fukayama, Masashi

doi:10.1158/0008-5472.can-07-3027

Cited by 87 publications

(80 citation statements)

References 29 publications

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“…However, AGS-EBV, which expresses LMP2A, showed a similar expression of p53 with AGS. In our experiment, LMP2A and EBNA1 might have induced chemoresistance through up-regulation of survivin in EBVpositive cells (Hino et al, 2008;Lu et al, 2011). Consistently, higher survivin expression was evident in EBV-positive GC cells than in EBV-negative GC cells, not only at basal level but also following 30 nM docetaxel treatment.…”

Section: Discussionsupporting

confidence: 78%

Association between Epstein-Barr Virus Infection and Chemoresistance to Docetaxel in Gastric Carcinoma

Shin

Kim

Lee

2011

Molecules and Cells

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Epstein-Barr virus (EBV) is associated with human cancers such as nasopharyngeal carcinoma, Burkitt's lymphoma, Hodgkin's disease, and gastric carcinoma (GC). EBV is associated with about 10% of all GC cases globally. EBV-associated GC has distinct features from EBV-negative GC. However, it is still unclear if EBV infection has any effect on GC chemoresistance. Cell proliferation assay, cell cycle analysis, and active caspase Western blot revealed that the EBV-positive GC cell line (AGS-EBV) showed chemoresistance to docetaxel compared to the EBV-negative GC cell line (AGS). Docetaxel treatment increased expression of Bax similarly in AGS and AGS-EBV cell lines. However, Bcl-2 induction was markedly higher in AGS-EBV cells, after docetaxel treatment. Although docetaxel increased the expression of p53 to a similar extent in both cell lines, induction of p21 in AGS-EBV cells was lower than in AGS cells. Furthermore, expression of survivin was higher in AGS-EBV cells than in AGS cells following docetaxel treatment as well as at basal state. EBVlytic gene expression was induced by docetaxel treatment in AGS-EBV cells. The results suggest that EBV infection and lytic induction confers chemoresistance to GC, possibly by regulating cellular and EBV latent and lytic gene expression.

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Section: Discussionsupporting

confidence: 78%

Association between Epstein-Barr Virus Infection and Chemoresistance to Docetaxel in Gastric Carcinoma

Shin

Kim

Lee

2011

Molecules and Cells

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“…The process involves a series of tumor suppressor genes (eg, p14, p15, p16, APC, CDH, MGMT and PTEN), which result in uncontrolled cell growth. 20,21 Of note, although microsatellite-instable gastric adenocarcinomas are also associated with hypermethylation and silencing of genes (and their promoters) in a distinctive pattern. EBV gastric cancers having a more extensive pattern of methylation of promoter and non-promoter CpG islands.…”

Section: Discussionmentioning

confidence: 99%

A protein and mRNA expression-based classification of gastric cancer

et al. 2016

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The overall survival of gastric carcinoma patients remains poor despite improved control over known risk factors and surveillance. This highlights the need for new classifications, driven towards identification of potential therapeutic targets. Using sophisticated molecular technologies and analysis, three groups recently provided genetic and epigenetic molecular classifications of gastric cancer (The Cancer Genome Atlas, 'Singapore-Duke' study, and Asian Cancer Research Group). Suggested by these classifications, here, we examined the expression of 14 biomarkers in a cohort of 146 gastric adenocarcinomas and performed unsupervised hierarchical clustering analysis using less expensive and widely available immunohistochemistry and in situ hybridization. Ultimately, we identified five groups of gastric cancers based on Epstein-Barr virus (EBV) positivity, microsatellite instability, aberrant E-cadherin, and p53 expression; the remaining cases constituted a group characterized by normal p53 expression. In addition, the five categories correspond to the reported molecular subgroups by virtue of clinicopathologic features. Furthermore, evaluation between these clusters and survival using the Cox proportional hazards model showed a trend for superior survival in the EBV and microsatellite-instable related adenocarcinomas. In conclusion, we offer as a proposal a simplified algorithm that is able to reproduce the recently proposed molecular subgroups of gastric adenocarcinoma, using immunohistochemical and in situ hybridization techniques. Gastric carcinoma is the fifth most common malignancy and the third leading cause of cancer-related death worldwide. Despite better control over known risk factors and development of new chemotherapeutic and targeted agents, in the United States, the 5-year overall survival for gastric cancer patients is only 29%. 1 With regard to patient stratification, although several morphologic classifications have been developed, one broadly used system is the Lauren classification, which divides gastric adenocarcinoma into intestinal and diffuse types. 2 The simple two-tiered classification gives a general understanding of the histogenesis and biology of gastric cancer, and has been particularly helpful in evaluating the epidemiologic data. Another widely used system is the WHO classification, which is based on more precise histologic patterns. It is an all-inclusive system, which recognizes all the rare subtypes that were not identified in the Lauren classification. 3 Nevertheless, its clinical utility is doubtful as there is little difference in outcomes between the distinct histological subgroups.Following the successful Trastuzumab for Gastric Cancer (ToGA) trial, the only validated predictive biomarker for personalized therapy of gastric cancer is limited to human epidermal growth factor receptor (Her2) protein expression. 4 Recently, anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody (ramucirumab) has been FDA approved, and anti-epidermal growth factor receptor (EGFR) an...

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“…Protein expression was evaluated by immunohistochemistry in GC tissues, which were resected for the treatment of GC at Tokyo University Hospital between 1993 and 1997. Tissue microarray (TMA) was constructed from 10% formalin-fixed and paraffin-embedded blocks of GC tissues, as reported previously (28). All cases of GC were histologically diagnosed according to the Japanese Classification of Gastric Carcinoma (29) and Lauren's classification (30).…”

Section: Methodsmentioning

confidence: 99%

“…Based on the concurrent occurrence of both abnormalities in EBVassociated GC, the underlying mechanism was investigated further using the recently characterized experimental systems, in which latency I pattern of EBV latent genes is faithfully reiterated in EBVinfected GC cell lines (28). The aim of the present study was to clarify how the host-virus interaction alters the epigenetics of the host cells, which leads to the neoplastic growth of stomach epithelial cells infected with EBV.…”

Section: Introductionmentioning

confidence: 98%

Activation of DNA Methyltransferase 1 by EBV Latent Membrane Protein 2A Leads to Promoter Hypermethylation of PTEN Gene in Gastric Carcinoma

et al. 2009

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CpG island promoter methylation of tumor suppressor genes is one of the most characteristic abnormalities in EBVassociated gastric carcinoma (GC). Aberrant promoter methylation and expression loss of PTEN were evaluated in cancer tissues of GC by methylation-specific PCR and immunohistochemistry, respectively, showing that both abnormalities occurred concurrently in EBV-associated GC. PTEN abnormalities were reiterated in GC cell lines MKN-1 and MKN-7 infected with recombinant EBV, and DNA methyltransferase 1 (DNMT1) was commonly overexpressed in both cell lines. Stable and transient transfection systems in MKN-1 similarly showed that viral latent membrane protein 2A (LMP2A) upregulated DNMT1, leading to an increase in methylation of the PTEN promoter. Importantly, the level of phosphorylated signal transducer and activator of transcription 3 (pSTAT3) increased in the nuclei of LMP2A-expressing GC cells, and knockdown of STAT3 counteracted LMP2A-mediated DNMT1 overexpression. Immunohistochemistry for both pSTAT3 and DNMT1 showed diffuse labeling in the nuclei of the cancer cells in GC tissues, especially in EBV-associated GC. Taken together, LMP2A induces the phosphorylation of STAT3, which activates DNMT1 transcription and causes PTEN expression loss through CpG island methylation of the PTEN promoter in EBV-associated GC. LMP2A plays an essential role in the epigenetic abnormalities in host stomach cells and in the development and maintenance of EBV-associated cancer.

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

Cited by 87 publications

References 29 publications

Association between Epstein-Barr Virus Infection and Chemoresistance to Docetaxel in Gastric Carcinoma

Association between Epstein-Barr Virus Infection and Chemoresistance to Docetaxel in Gastric Carcinoma

A protein and mRNA expression-based classification of gastric cancer

Activation of DNA Methyltransferase 1 by EBV Latent Membrane Protein 2A Leads to Promoter Hypermethylation of PTEN Gene in Gastric Carcinoma

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