DNA methylation in gastric cancer, related toHelicobacter pyloriand Epstein-Barr virus

Epstein–Barr-virus-associated gastric carcinoma (EBVaGC), first reported in 1992, currently accounts for 10% of all gastric carcinoma worldwide. EBVaGC has unique DNA hypermethylation phenotypes that allow for higher proportions of DNA methylation than any other gastric cancer. CpG islands in the gene promoter region are one of the major regions in which DNA methylation controls gene transcription. Despite cisplatin-based chemotherapy being one of the standard treatment regimens for advanced gastric cancer, including EBVaGC, cisplatin alone or in combination with 5-fluorouracil has been limited by its less potent anticancer activity and the occurrence of cisplatin resistance. Accordingly, the current study evaluated the anticancer activities of a combination of cisplatin and 5-Azacytidine (5-AZA) against EBVaGC. Our findings showed that cisplatin upregulated the DNMT3A gene, whereas shRNA-targeted removal of DNMT3A mRNA contributed to cisplatin-mediated EBV lytic reactivation. Moreover, the removal of DNMT3A mRNA upregulated the ATM gene through DNA demethylation on the ATM promoter. Furthermore, CRISPR/Cas9-targeted removal of the ATM gene resulted in significantly reduced cell susceptibility and EBV lytic reactivation by a combination of cisplatin and DNMT3A inhibitor 5-AZA. Finally, 5-AZA exhibited a synergistic effect with cisplatin in anti-EBV and anti-EBVaGC activities by increasing drug susceptibility and EBV lytic reactivation. The aforementioned results suggest that cisplatin combined with DNA methylation inhibitors could be a novel therapeutic approach for EBVaGC.

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

Cancer Cell International ◽

10.1186/s12935-021-02077-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Zeyang Wang ◽

Zhi Lv ◽

Qian Xu ◽

Liping Sun ◽

Yuan Yuan

Keyword(s):

Gastric Cancer ◽

Functional Analysis ◽

Protein Expression ◽

Epstein Barr Virus ◽

Protein Profile ◽

Expression Patterns ◽

Clinicopathological Parameters ◽

Differential Proteomics ◽

Barr Virus ◽

Epstein Barr

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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