Identification of differential proteomics in Epstein-Barr virus-associated gastric cancer and related functional analysis

Abstract Background Epstein-Barr virus-associated gastric cancer (EBVaGC) is the most common EBV-related malignancy. A comprehensive research for the protein expression patterns in EBVaGC established by high-throughput assay remains lacking. In the present study, the protein profile in EBVaGC tissue was explored and related functional analysis was performed. Methods Epstein-Barr virus-encoded RNA (EBER) in situ hybridization (ISH) was applied to EBV detection in GC cases. Data-independent acquisition (DIA) mass spectrometry (MS) was performed for proteomics assay of EBVaGC. Functional analysis of identified proteins was conducted with bioinformatics methods. Immunohistochemistry (IHC) staining was employed to detect protein expression in tissue. Results The proteomics study for EBVaGC was conducted with 7 pairs of GC cases. A total of 137 differentially expressed proteins in EBV-positive GC group were identified compared with EBV-negative GC group. A PPI network was constructed for all of them, and several proteins with relatively high interaction degrees could be the hub genes in EBVaGC. Gene enrichment analysis showed they might be involved in the biological pathways related to energy and biochemical metabolism. Combined with GEO datasets, a highly associated protein (GBP5) with EBVaGC was screened out and validated with IHC staining. Further analyses demonstrated that GBP5 protein might be associated with clinicopathological parameters and EBV infection in GC. Conclusions The newly identified proteins with significant differences and potential central roles could be applied as diagnostic markers of EBVaGC. Our study would provide research clues for EBVaGC pathogenesis as well as novel targets for the molecular-targeted therapy of EBVaGC.

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The Transcriptomic Landscape of Gastric Cancer: Insights into Epstein-Barr Virus Infected and Microsatellite Unstable Tumors

International Journal of Molecular Sciences ◽

10.3390/ijms19072079 ◽

2018 ◽

Vol 19 (7) ◽

pp. 2079 ◽

Cited By ~ 8

Author(s):

Irene Gullo ◽

Joana Carvalho ◽

Diana Martins ◽

Diana Lemos ◽

Ana Monteiro ◽

...

Keyword(s):

Gastric Cancer ◽

Protein Expression ◽

Epstein Barr Virus ◽

Molecular Subtype ◽

Expression Patterns ◽

Therapeutic Implications ◽

Barr Virus ◽

Epstein Barr ◽

Nanostring Technology ◽

L1 Protein

Background: Epstein-Barr Virus (EBV) positive and microsatellite unstable (MSI-high) gastric cancer (GC) are molecular subgroups with distinctive molecular profiles. We explored the transcriptomic differences between EBV+ and MSI-high GCs, and the expression of current GC immunotherapy targets such as PD-1, PD-L1, CTLA4 and Dies1/VISTA. Methods: Using Nanostring Technology and comparative bioinformatics, we analyzed the expression of 499 genes in 46 GCs, classified either as EBV positive (EBER in situ hybridization) or MSI-high (PCR/fragment analysis). PD-L1 protein expression was assessed by immunohistochemistry. Results: From the 46 GCs, 27 tested MSI-high/EBV−, 15 tested MSS/EBV+ and four tested MSS/EBV−. The Nanostring CodeSet could segregate GCs according to MSI and, to a lesser extent, EBV status. Functional annotation of differentially expressed genes associated MSI-high/EBV− GCs with mitotic activity and MSS/EBV+ GCs with immune response. PD-L1 protein expression, evaluated in stromal immune cells, was lower in MSI-high/EBV− GCs. High mRNA expression of PD-1, CTLA4 and Dies1/VISTA and distinctive PD-1/PD-L1 co-expression patterns (PD-1high/PD-L1low, PD-1high/PDL1high) were associated with MSS/EBV+ molecular subtype and gastric cancer with lymphoid stroma (GCLS) morphological features. Conclusions: EBV+ and MSI-high GCs present distinct transcriptomic profiles. GCLS/EBV+ cases frequently present co-expression of multiple immunotherapy targets, a finding with putative therapeutic implications.

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Andrographolide Inhibits Lytic Reactivation of Epstein–Barr Virus by Modulating Transcription Factors in Gastric Cancer

Microorganisms ◽

10.3390/microorganisms9122561 ◽

2021 ◽

Vol 9 (12) ◽

pp. 2561

Author(s):

Praphatson Malat ◽

Tipaya Ekalaksananan ◽

Chukkris Heawchaiyaphum ◽

Supawadee Suebsasana ◽

Sittiruk Roytrakul ◽

...

Keyword(s):

Gastric Cancer ◽

Transcription Factors ◽

Protein Expression ◽

Epstein Barr Virus ◽

Expression Patterns ◽

Chemical Constituent ◽

Barr Virus ◽

Lytic Reactivation ◽

Epstein Barr ◽

Apoptosis Related Protein

Andrographolide is the principal bioactive chemical constituent of Andrographis paniculata and exhibits activity against several viruses, including Epstein–Barr virus (EBV). However, the particular mechanism by which andrographolide exerts an anti-EBV effect in EBV-associated gastric cancer (EBVaGC) cells remains unclear. We investigated the molecular mechanism by which andrographolide inhibits lytic reactivation of EBV in EBVaGC cells (AGS-EBV cell line) using proteomics and bioinformatics approaches. An andrographolide treatment altered EBV protein-expression patterns in AGS-EBV cells by suppressing the expression of EBV lytic protein. Interestingly cellular transcription factors (TFs), activators for EBV lytic reactivation, such as MEF2D and SP1, were significantly abolished in AGS-EBV cells treated with andrographolide and sodium butyrate (NaB) compared with NaB-treated cells. In contrast, the suppressors of EBV lytic reactivation, such as EZH2 and HDAC6, were significantly up-regulated in cells treated with both andrographolide and NaB compared with NaB treatment alone. In addition, bioinformatics predicted that HDAC6 could interact directly with MEF2D and SP1. Furthermore, andrographolide significantly induced cell cytotoxicity and apoptosis of AGS-EBV cells by induction of apoptosis-related protein expression. Our results suggest that andrographolide inhibits EBV lytic reactivation by inhibition of host TFs, partially through the interaction of HDAC6 with TFs, and induces apoptosis of EBVaGC cells.

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Clinical Significance of p53 Protein Expression, Beta-catenin Expression and HER2 Expression for Epstein-Barr Virus-associated Gastric Cancer

Chonnam Medical Journal ◽

10.4068/cmj.2017.53.2.140 ◽

2017 ◽

Vol 53 (2) ◽

pp. 140 ◽

Cited By ~ 3

Author(s):

Dong Won Baek ◽

Byung Woog Kang ◽

Soyoon Hwang ◽

Jong Gwang Kim ◽

An Na Seo ◽

...

Keyword(s):

Gastric Cancer ◽

Protein Expression ◽

Clinical Significance ◽

Epstein Barr Virus ◽

P53 Protein ◽

Beta Catenin ◽

Her2 Expression ◽

Barr Virus ◽

P53 Protein Expression ◽

Epstein Barr

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Relationship of intratumoural protein expression patterns to age and Epstein-Barr virus status in classical Hodgkin lymphoma

European Journal Of Haematology ◽

10.1111/ejh.12463 ◽

2014 ◽

Vol 95 (2) ◽

pp. 137-149 ◽

Cited By ~ 6

Author(s):

Maja Ludvigsen ◽

Peter Kamper ◽

Stephen J. Hamilton-Dutroit ◽

Knud Bendix ◽

Michael B. Møller ◽

...

Keyword(s):

Protein Expression ◽

Hodgkin Lymphoma ◽

Epstein Barr Virus ◽

Expression Patterns ◽

Classical Hodgkin Lymphoma ◽

Barr Virus ◽

Epstein Barr ◽

Relationship Of

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The clinicopathological significance and predictive value for immunotherapy of programmed death ligand-1 expression in Epstein-Barr virus-associated gastric cancer

OncoImmunology ◽

10.1080/2162402x.2021.1938381 ◽

2021 ◽

Vol 10 (1) ◽

pp. 1938381

Author(s):

Xiao-Li Wei ◽

Qian-Wen Liu ◽

Fu-Rong Liu ◽

Sha-Sha Yuan ◽

Xiao-Fen Li ◽

...

Keyword(s):

Gastric Cancer ◽

Predictive Value ◽

Epstein Barr Virus ◽

Programmed Death Ligand 1 ◽

Barr Virus ◽

Programmed Death ◽

Clinicopathological Significance ◽

Epstein Barr

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Intratumoral CXCR5+CD8+T associates with favorable clinical outcomes and immunogenic contexture in gastric cancer

Nature Communications ◽

10.1038/s41467-021-23356-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jieti Wang ◽

Ruochen Li ◽

Yifan Cao ◽

Yun Gu ◽

Hanji Fang ◽

...

Keyword(s):

Gastric Cancer ◽

Overall Survival ◽

T Cells ◽

Epstein Barr Virus ◽

Effector Memory ◽

Feature Identification ◽

Barr Virus ◽

T Cell Infiltration ◽

Epstein Barr ◽

Gastric Cancer Patients

AbstractStudies that examined an association between CD8+T and prognosis in gastric cancer are inconsistent, and a distinct population of CXCR5+CD8+T associated with better overall survival has been reported among various malignancies. Here, we show that the abundance of intratumoral CXCR5+CD8+T cells is associated with better overall survival in patients with gastric cancer. Patients with TNM II + III gastric cancer with higher intratumoral CXCR5+CD8+T cell infiltration are more likely to benefit from adjuvant chemotherapy. Microsatellite-unstable and Epstein–Barr virus positive tumors are enriched with CXCR5+CD8+T cells. Gastric cancer infiltrating CXCR5+CD8+T cells represent a specific subtype of stem-like CD8+T with effector memory feature. Identification of the clinical significance and phenotype of gastric cancer infiltrating CXCR5+CD8+T provides a roadmap for patient stratification and trials of targeted therapies.

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