Adenosine Induces EBV Lytic Reactivation through ADORA1 in EBV-Associated Gastric Carcinoma

Choi, Su Jin; Ryu, Eunhyun; Lee, Seulki; Huh, Sora; Shin, Yu Su; Kang, Byung Woog; Kim, Jong Gwang; Cho, Hyosun; Kang, Hyojeung

doi:10.3390/ijms20061286

Cited by 12 publications

(10 citation statements)

References 43 publications

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“…Moreover, the canonical NF-κB signalling pathway is constitutively activated, and this plays an essential role in EBVaGC tumorigenesis 16 . ADORA1 has been reported to suppress BZLF1 induction, increase tumour cell growth with EBV infection and inhibit sensitivity to the cytotoxic effects of antiviral and anticancer agents 17 . Thus, therapy selection based on the mechanism of tumour development is required, and it is important to diagnose EBVaGC prior to treatment.…”

Section: Introductionmentioning

confidence: 99%

CXCR4 induces cell autophagy and maintains EBV latent infection in EBVaGC

et al. 2020

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Rationale: Epstein-Barr virus (EBV) is found in ~7% of gastric carcinoma cases worldwide, and all tumour cells harbour the clonal EBV genome. EBV can regulate pathways and protein expression to induce gastric carcinoma; however, the molecular mechanism underlying EBV-associated gastric carcinoma (EBVaGC) remains elusive. Methods: GEO microarray and molecular experiments were performed to compare CXCR4 expression between EBV-positive and EBV-negative gastric carcinoma (EBVnGC). Transfections with LMP2A plasmid or siRNA were carried out to assess the role of LMP2A in CXCR4 expression. The effects and mechanisms of CXCR4 on cell autophagy were analysed in vitro using molecular biological and cellular approaches. Additionally, we also determined the regulatory role of CXCR4 in latent EBV infection. Results: CXCR4 expression was significantly upregulated in EBVaGC tissues and cell lines. LMP2A could induce AKT phosphorylation to increase NRF1 expression, thereby binding to the CXCR4 promoter to increase its transcriptional level. Moreover, CXCR4 promoted ZEB1 expression to upregulate ATG7 synthesis, which could then activate autophagy. Moreover, CXCR4 increased the number of cells entering the G2/M phase and inhibited cell apoptosis via the autophagy pathway. Finally, CXCR4 knockdown was associated with elevated BZLF1 expression, but this effect was not influenced by autophagy. Conclusions: Our data suggested new roles for CXCR4 in autophagy and EBV replication in EBVaGC, which further promoted cell survival and persistent latent infection. These new findings can lead to further CXCR4-based anticancer therapy.

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Section: Introductionmentioning

confidence: 99%

CXCR4 induces cell autophagy and maintains EBV latent infection in EBVaGC

et al. 2020

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“…[43][44][45][46] Recent reports on cancers of epithelial origin indicate that, in addition to nasopharyngeal cancer, EBV infection is also closely associated with approximately 10% of gastric cancers, which are known as EBV-associated gastric carcinomas (EBVaGC). 47,48 In addition, recent studies have revealed an association between EBV infection and certain breast cancers. 49 EBV was the first virus to be identified as an oncogenic virus, and as the spectrum of cancers caused by this virus widened, mechanisms underlying its pathogenicity came under increasing scrutiny.…”

Section: Discussionmentioning

confidence: 99%

“…EBV infection is a direct cause of NPC, which is invasive and metastatic, often resulting in death 43‐46 . Recent reports on cancers of epithelial origin indicate that, in addition to nasopharyngeal cancer, EBV infection is also closely associated with approximately 10% of gastric cancers, which are known as EBV‐associated gastric carcinomas (EBVaGC) 47,48 . In addition, recent studies have revealed an association between EBV infection and certain breast cancers 49 .…”

Section: Discussionmentioning

confidence: 99%

EBV‐miR‐BART12 accelerates migration and invasion in EBV‐associated cancer cells by targeting tubulin polymerization‐promoting protein 1

Wang

Fang

et al. 2020

FASEB j.

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Epstein-Barr virus (EBV) infection leads to cancers with an epithelial origin, such as nasopharyngeal cancer and gastric cancer, as well as multiple blood cell-based malignant tumors, such as lymphoma. Interestingly, EBV is also the first virus found to carry genes encoding miRNAs. EBV encodes 25 types of pre-miRNAs which are finally processed into 44 mature miRNAs. Most EBV-encoded miRNAs were found to be involved in the occurrence and development of EBV-related tumors. However, the function of EBV-miR-BART12 remains unclear. The findings of the current study revealed that EBV-miR-BART12 binds to the 3'UTR region of Tubulin Polymerization-Promoting Protein 1 (TPPP1) mRNA and downregulates TPPP1, thereby promoting the invasion and migration of EBV-related cancers, such as nasopharyngeal cancer and gastric cancer. The mechanism underlying this process was found to be the inhibition of TPPP1 by EBV-miRNA-BART12, which, in turn, inhibits the acetylation of α-tubulin, and promotes the dynamic assembly of microtubules, remodels the cytoskeleton, and enhances the acetylation of β-catenin. β-catenin activates epithelial to mesenchymal transition (EMT). These two processes synergistically promote the invasion and metastasis of tumor cells. To the best of our knowledge, this is the first study to reveal the role of EBV-miRNA-BART12 in the development of EBV-related tumors as well as the mechanism underlying this process, and suggests potential targets and strategies for the treatment of EBV-related tumors.

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“…The following cycles thermal conditions were used: 95°C for 10 min; cycles of 95°C for sec, 55°C for 10 sec, and 72°C for 10 sec; 95°C for 5 sec; followed by 65°C for 1 min. In case of necessity, semi-quantitative PCR (sqPCR) was also conducted as previously described [37]. PCR products were amplified in a 25 µL reaction solution containing 5 µL of 5× reaction mix, 5 µL of 5× TuneUp solution, 1 µL of Taq-plus polymerase, and 2.5 µL of 10 pmol forward/reverse primer.…”

Section: Real-time Quantitative Pcr (Qpcr)mentioning

confidence: 99%

Structure-based mapping of the TβRI and TβRII receptor binding sites of the parasitic TGF-β mimic, Hp-TGM

Mukundan

Byeon

Hinck

et al. 2020

Preprint

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TGF-β is a secreted signaling protein involved in many physiological processes: organ development, production and maintenance of the extracellular matrix, as well as regulation of the adaptive immune system. As a cytokine, TGF-β stimulates the differentiation of CD4+ T-cells into regulatory T-cells (Tregs) that act to promote peripheral immune tolerance. The murine parasite Heligmosomoides polygyrus takes advantage of this pathway to induce inducing Foxp3+ Tregs in a similar manner using a TGF-β mimic (TGM), comprised of five tandem complement control protein (CCP) domains, designated D1-D5. Despite having no structural homology to TGF-β or to TGF-β family proteins, TGM binds directly to the TGF-β type I and type II receptors, TβRI and TβRII. To further investigate, NMR titration, and SPR and ITC binding experiments were performed, showing that TGM-D2, with the aid of D1, binds TβRI and TGM-D3 binds TβRII. Competition ITC experiments showed that TGM-D3 competes with TGF-β for binding to TβRII, consistent with TGM-D3-induced NMR chemical shift perturbations of TβRII which aligned with the solvent inaccessible areas of TβRII upon binding TGF-β. Thus, TGM-D3 binds to the same edged β-strand of TβRII that is used to bind TGF-β. Competition ITC experiments demonstrated that TGM-D1D2 and TGF-β3:TβRII compete for binding to TβRI, while TGM-D2-induced NMR chemical shift perturbation of TβRI showed that TGM-D2 binds to the same pre-helix extension of TβRI as does the TGF-β/TβRII binary complex. The solution structure of TGM-D3 revealed that while it has the overall structure of a CCP domain, TGM-D3 has an insertion in the hypervariable loop uncommon to CCP domains. These findings suggest that parasitic TGM, despite its lack of structural similarity to TGF-β, evolved to take advantage of the binding regions of the mammalian TGF-β type I and type II receptors. The structure of this TGM domain, along with the predicted structure of other H. polygyrus secreted proteins reported in the literature, suggest that TGM is part of a larger family of evolutionarily-adapted immunomodulatory CCP-containing proteins.

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Adenosine Induces EBV Lytic Reactivation through ADORA1 in EBV-Associated Gastric Carcinoma

Cited by 12 publications

References 43 publications

CXCR4 induces cell autophagy and maintains EBV latent infection in EBVaGC

CXCR4 induces cell autophagy and maintains EBV latent infection in EBVaGC

EBV‐miR‐BART12 accelerates migration and invasion in EBV‐associated cancer cells by targeting tubulin polymerization‐promoting protein 1

Structure-based mapping of the TβRI and TβRII receptor binding sites of the parasitic TGF-β mimic, Hp-TGM

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