Epstein–Barr virus latent membrane protein 2A mediated activation of Sonic Hedgehog pathway induces HLA class Ia downregulation in gastric cancer cells

Pal, Amit Kumar; Banerjee, Subrata

doi:10.1016/j.virol.2015.05.007

Cited by 26 publications

(25 citation statements)

References 36 publications

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“…The EBV-encoded lytic proteins BILF1 and BDLF3 increase degradation of MHC-I. 31,32 Also, the latently-expressed EBV membrane protein 2A (LMP2A) can induce downregulation of MHC-I through the sonic hedgehog pathway, 33 and EBV downregulates several surface markers in primary infected B-cells including B7-2. 34 Other viruses use different strategies.…”

Section: Introductionmentioning

confidence: 99%

Pomalidomide increases immune surface marker expression and immune recognition of oncovirus-infected cells

et al. 2018

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Most chronic viruses evade T-cell and natural killer (NK) immunity through downregulation of immune surface markers. Previously we showed that Pomalidomide (Pom) increases surface expression of major histocompatibility complex class I (MHC-I) in Kaposi sarcoma-associated herpesvirus-infected latent and lytic cells and restores ICAM-1 and B7-2 in latent cells. We explored the ability of Pom to increase immune surface marker expression in cells infected by other chronic viruses, including human T-cell leukemia virus type-1 (HTLV-1), Epstein-Barr virus (EBV), human papilloma virus (HPV), Merkel cell polyoma virus (MCV), and human immunodeficiency virus type-1 (HIV-1). Pom increased MHC-1, ICAM-1, and B7-2/CD86 in immortalized T-cell lines productively infected with HTLV-1 and also significantly increased their susceptibility to NK cell-mediated cytotoxicity. Pom enhancement of MHC-I and ICAM-1 in primary cells infected with HTLV-1 was abrogated by knockout of HTLV-1 orf-1. Pom increased expression of ICAM-1, B7-2 and MHC class I polypeptide related sequence A (MICA) surface expression in the EBV-infected Daudi cells and increased their T-cell activation and susceptibility to NK cells. Moreover, Pom increased expression of certain of these surface markers on Akata, Raji, and EBV lymphoblastic cell lines. The increased expression of immune surface markers in these virus-infected lines was generally associated with a decrease in IRF4 expression. By contrast, Pom treatment of HPV, MCV and HIV-1 infected cells did not increase these immune surface markers. Pom and related drugs may be clinically beneficial for the treatment of HTLV-1 and EBV-induced tumors by rendering infected cells more susceptible to both innate and adaptive host immune responses.

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Section: Introductionmentioning

confidence: 99%

Pomalidomide increases immune surface marker expression and immune recognition of oncovirus-infected cells

et al. 2018

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“…Transcription Factors (TFs) including Nuclear Factor kappa-lightchain-enhancer of activated B cells (NFkB), Class II major histocompatibility complex Transactivator (CIITA), and Regulatory Factor X (RFX5) are reported to bind the promoter region at the enhancer sites. We previously showed decreased protein expression of the above-mentioned transcription factors in LMP2A expressing gastric cancer cells 19 . A decrease in transcript-level expression of HLA-ABC in gastric cancer cell, AGS expressing LMP2A gene was evaluated through quantitative Real-Time PCR (qRT-PCR) ( Fig.…”

Section: Resultsmentioning

confidence: 91%

“…EBV latent protein, LMP2A cDNA was cloned within the EcoR1 site of the pcDNA 3.1 vector and stably transfected into EBV-negative gastric cancer cell, AGS. Clones which showed expression pattern of LMP2A similar to that of EBV-positive Korean gastric cancer cell, SNU-719 were selected for the study 12,19 . Protein level measurement of LMP2A expression was estimated in AGS and AGS-LMP2A cells ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…HLA is reported to present intracellular peptides derived from viral and tumour antigens to the counteracting T-cell receptors, thus resulting in recognition of virus-infected tumour cells by CTLs. We previously reported decreased HLA-ABC surface expression through EBV latent protein, LMP2A in EBVaGC 18,19 . However, mechanisms responsible for HLA-ABC gene downregulation aside from its decreased surface-level expression in EBVaGC are yet to be fully investigated.…”

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confidence: 93%

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Downregulation of HLA-ABC expression through promoter hypermethylation and downmodulation of MIC-A/B surface expression in LMP2A-positive epithelial carcinoma cell lines

Singh

Banerjee

2020

Sci Rep

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Virus (eBV) is a human herpesvirus, and has been reported to be associated with nasopharyngeal carcinoma, gastric carcinoma, Burkitt's lymphoma and Hodgkin's lymphoma. in most of the associated tumors, the virus remains in a latently infected state. During latency, eBV expresses Latent Membrane Protein 2A (LMP2A) along with few other genes. We previously showed that LMP2A causes downregulation of HLA-ABC surface expression in EBV associated gastric carcinomas. However, the mechanism that leads to this downregulation remain unclear. We therefore analyzed methylation-mediated regulation of HLA-ABC expression by LMP2A. Interestingly, according to the 'missing self' hypothesis, when there is a decrease in HLA-ABc surface expression, expression of NKG2D ligands' must be upregulated to facilitate killing by Natural Killer (NK) cells. Analysis of NKG2D ligands' expression, revealed downregulation of MIC-A/B surface expression in response to LMP2A. Furthermore, the role of Unfolded Protein Response (UPR) in the regulation of MIC-A/B surface expression in cells expressing LMP2A was also investigated. Protein Disulfide Isomerase (PDI) mediated inhibition of MIC-A/B surface expression was observed in LMP2A expressing cells. Our current findings provide new insights in LMP2A arbitrated dysregulation of host immune response in epithelial cell carcinomas. Host immune response plays pivotal role in development and progression of cancer. CTLs and NK cells play important role in recognition and elimination of virus-infected cells. Downmodulation of the HLA class I antigen processing pathway 1,2 along with proteasome subunits act as strategies utilised by the viruses to overcome host immune response. Transporter associated with antigen presentation, β-microglobulin and HLA class-I heavy chains are also reported to be targeted during viral infection 3. Alternatively, tumour immune evasion mechanism involves internalization and shedding of NKG2Dligands' , MHC class I chain-related proteins A and B (MIC-A and MIC-B) and UL16-binding proteins (ULBPs), ensuing inhibition of NK cell-mediated cytotoxicity 4,5. EBV, γ-human herpes virus, is known to be associated with various malignancies such as Burkitt's Lymphoma, Hodgkin's Lymphoma, Nasopharyngeal Carcinoma, Gastric Carcinoma, and Breast Cancer 6-9. EBV-associated gastric carcinoma (EBVaGC), an epithelial cell origin carcinoma has recently gained importance 10. EBV manifests lifelong latent infection in most of the EBV-associated malignant neoplasm. EBV establishes latent infection in most of the tumors where it expresses Latent Membrane Protein 2A (LMP2A) along with other EBV-encoded genes 6. The viral oncoprotein, LMP2A plays important role in the maintenance of latency and is recognized to

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“…For instance, in human immunodeficiency virus‐1 (HIV‐1) infection, a spliced form of Tat decreases the HLA class I promoter activity through the CAT and TATA box . In gastric cancer cells, the latent membrane protein 2A (LMP2A) of Epstein–Barr virus (EBV) down‐regulates HLA‐A, ‐B and ‐C mRNA expression through the hedgehog pathway and more specially via Gli1 . IFN‐γ‐induced expression of MHC class I is hampered in hepatitis‐C virus (HCV)‐infected cells through the activation of protein kinase R (PKR).…”

Section: Hla Class I Pattern Of Expression In Pathological Conditionsmentioning

confidence: 99%

Expression of classical HLA class I molecules: regulation and clinical impacts

René

Lozano

Eliaou

2016

HLA

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Human leukocyte antigen (HLA) class I genes are ubiquitously expressed, but in a tissue specific-manner. Their expression is primarily regulated at the transcriptional level and can be modulated both positively and negatively by different stimuli. Advances in sequencing technologies led to the identification of new regulatory variants located in the untranslated regions (UTRs), which could influence the expression. After a brief description of the mechanisms underlying the transcriptional regulation of HLA class I genes expression, we will review how the expression levels of HLA class I genes could affect biological and pathological processes. Then, we will discuss on the differential expression of HLA class I genes according to the locus, allele and UTR polymorphisms and its clinical impact. This interesting field of study led to a new dimension of HLA typing, going beyond a qualitative aspect.

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Epstein–Barr virus latent membrane protein 2A mediated activation of Sonic Hedgehog pathway induces HLA class Ia downregulation in gastric cancer cells

Cited by 26 publications

References 36 publications

Pomalidomide increases immune surface marker expression and immune recognition of oncovirus-infected cells

Pomalidomide increases immune surface marker expression and immune recognition of oncovirus-infected cells

Downregulation of HLA-ABC expression through promoter hypermethylation and downmodulation of MIC-A/B surface expression in LMP2A-positive epithelial carcinoma cell lines

Expression of classical HLA class I molecules: regulation and clinical impacts

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