Epstein-Barr virus stably confers an invasive phenotype to epithelial cells through reprogramming of the WNT pathway

Birdwell, Christine; Prasai, Kanchanjunga; Dykes, Samantha S.; Jia, Yali; Munroe, Tawsha G.C.; Bienkowska-Haba, Malgorzata; Scott, Rona S.

doi:10.18632/oncotarget.23824

Cited by 24 publications

(30 citation statements)

References 79 publications

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“…HPV E7 was sufficient to block EBV lytic replication, uncovering potential requirements for Rb, altered KLF4 activity, and/or additional regulators in the reduction of EBV replication in HPV-immortalized cells. In oral keratinocytes latently infected with EBV, we previously demonstrated an enhanced invasive phenotype and delayed differentiation (16,17). Taking these data together, we propose a model where HPV-induced cellular changes facilitate the establishment of a latent EBV infection.…”

Section: Discussionmentioning

confidence: 57%

“…We have shown that EBV-infected NOK exhibit a predominant latent gene expression profile (16). Importantly, we have reported that EBV-infected NOK undergo an epigenetic reprogramming, evidenced by DNA hypermethylation and altered gene expression that are retained following loss of the EBV genome from cells (16,17). Phenotypically, EBV-infected NOK and transiently infected cells showed delayed responses to differentiation induction and increased invasiveness (16,17).…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, we have reported that EBV-infected NOK undergo an epigenetic reprogramming, evidenced by DNA hypermethylation and altered gene expression that are retained following loss of the EBV genome from cells (16,17). Phenotypically, EBV-infected NOK and transiently infected cells showed delayed responses to differentiation induction and increased invasiveness (16,17). Changes to the Wnt pathway were observed, with increased expression of lymphoid enhancer factor 1 (LEF1) and WNT5A in EBV-infected NOK compared to their expression in parental controls (17).…”

Section: Discussionmentioning

confidence: 99%

“…Phenotypically, EBV-infected NOK and transiently infected cells showed delayed responses to differentiation induction and increased invasiveness (16,17). Changes to the Wnt pathway were observed, with increased expression of lymphoid enhancer factor 1 (LEF1) and WNT5A in EBV-infected NOK compared to their expression in parental controls (17). WNT5A is a transcriptional target of KLF4 that can rescue epithelial stratification in the absence of KLF4 (55).…”

Section: Discussionmentioning

confidence: 99%

“…We have shown that EBV can epigenetically reprogram epithelial cells, resulting in tumorigenic phenotypes that remain after loss of EBV genomes from cells. Epithelial cells either persistently or transiently infected with EBV exhibit enhanced invasiveness and delayed differentiation (16)(17)(18). EBV could therefore contribute to the invasive potential and poorly differentiated status often observed in HPV-pos OSCCs through virally induced epigenetic alterations as EBV transits through the epithelium.…”

mentioning

confidence: 99%

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Inhibition of Epstein-Barr Virus Replication in Human Papillomavirus-Immortalized Keratinocytes

Guidry

Myers

Bienkowska-Haba

et al. 2019

J Virol

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Epstein-Barr virus (EBV) is implicated in the pathogenesis of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OSCC). EBV-associated cancers harbor a latent EBV infection characterized by a lack of viral replication and the expression of viral oncogenes. Cellular changes promoted by HPV are comparable to those shown to facilitate EBV latency, though whether HPV-positive cells support a latent EBV infection has not been demonstrated. Using a model of direct EBV infection into HPV16-immortalized tonsillar cells grown in organotypic raft culture, we showed robust EBV replication in HPV-negative rafts but little to no replication in HPV-immortalized rafts. The reduced EBV replication was independent of immortalization, as human telomerase-immortalized normal oral keratinocytes supported robust EBV replication. Furthermore, we observed reduced EBV lytic gene expression and increased expression of EBER1, a noncoding RNA highly expressed in latently infected cells, in the presence of HPV. The use of human foreskin keratinocyte rafts expressing the HPV16 E6 and/or E7 oncogene(s) (HPV E6 and E7 rafts) showed that E7 was sufficient to reduce EBV replication. EBV replication is dependent upon epithelial differentiation and the differentiation-dependent expression of the transcription factors KLF4 and PRDM1. While KLF4 and PRDM1 levels were unaltered, the expression levels of KLF4 transcriptional targets, including late differentiation markers, were reduced in HPV E6 and E7 rafts compared to their levels in parental rafts. However, the HPV E7-mediated block in EBV replication correlated with delayed expression of early differentiation markers. Overall, this study reveals an HPV16-mediated block in EBV replication, through E7, that may facilitate EBV latency and long-term persistence in the tumor context. IMPORTANCE Using a model examining the establishment of EBV infection in HPV-immortalized tissues, we showed an HPV-induced interruption of the normal EBV life cycle reminiscent of a latent EBV infection. Our data support the notion that a persistent EBV epithelial infection depends upon preexisting cellular alterations and suggest the ability of HPV to promote such changes. More importantly, these findings introduce a model for how EBV coinfection may influence HPV-positive (HPV-pos) OSCC pathogenesis. Latently EBV-infected epithelial cells, as well as other EBV-associated head-and-neck carcinomas, exhibit oncogenic phenotypes commonly seen in HPV-pos OSCC. Therefore, an HPV-induced shift in the EBV life cycle toward latency would not only facilitate EBV persistence but also provide additional viral oncogene expression, which can contribute to the rapid progression of HPV-pos OSCC. These findings provide a step toward defining a role for EBV as a cofactor in HPV-positive oropharyngeal tumors.

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Inhibition of Epstein-Barr Virus Replication in Human Papillomavirus-Immortalized Keratinocytes

Guidry

Myers

Bienkowska-Haba

et al. 2019

J Virol

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Metagenomic analysis of primary colorectal carcinomas and their metastases identifies potential microbial risk factors

et al. 2021

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The paucity of microbiome studies at intestinal tissues has contributed to a yet limited understanding of potential viral and bacterial co-factors of colorectal cancer (CRC) carcinogenesis or progression. We analyzed whole-genome sequences of CRC primary tumours, their corresponding metastases and matched normal tissue for sequences of viral, phage and bacterial species. Bacteriome analysis showed Fusobacterium nucleatum, Streptococcus sanguinis, F. Hwasookii, Anaerococcus mediterraneensis and further species enriched in primary CRCs.The primary CRC of one patient was enriched for F. alocis, S. anginosus, Parvimonas micra and Gemella sp. λ48. Enrichment of Escherichia coli strains IAI1, SE11, K-12 and M8 was observed in metastases together with coliphages enterobacteria phage φ80 and Escherichia phage VT2φ_272. Virome analysis showed that phages were the most preponderant viral species (46%), the main families being Myoviridae, Siphoviridae and Podoviridae. Primary CRCs were enriched for bacteriophages, showing five phages (Enterobacteria, Bacillus, Proteus, Streptococcus phages) together with their pathogenic hosts in contrast to normal tissues. The most frequently detected, and Blast-confirmed, viruses included human endogenous retrovirus K113, human herpesviruses 7 and 6B, Megavirus chilensis, cytomegalovirus (CMV) and Epstein-Barr virus (EBV), with one patient showing EBV enrichment in primary tumour and metastases. EBV was PCR-validated in 80 pairs of CRC primary tumour and their corresponding normal tissues; in 21 of these pairs (26.3%), it was detectable in primary tumours only. The number of viral species was increased and bacterial species decreased in CRCs compared with normal tissues,and we could discriminate primary CRCs from metastases and normal tissues by applying the Hutcheson t-test on the Shannon indices based on viral and bacterial species. Taken together, our results descriptively support hypotheses on microorganisms as potential (co-)risk factors of CRC, and extend putative suggestions on critical microbiome species in CRC metastasis.

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Viruses in colorectal cancer

Marongiu

Allgayer

2021

Molecular Oncology

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Increasing evidence suggests that microorganisms might represent at least highly interesting cofactors in colorectal cancer (CRC) oncogenesis and progression. Still, associated mechanisms, specifically in colonocytes and their microenvironmental interactions, are still poorly understood. Although, currently, at least seven viruses are being recognized as human carcinogens, only three of these – Epstein–Barr virus (EBV), human papillomavirus (HPV) and John Cunningham virus (JCV) – have been described, with varying levels of evidence, in CRC. In addition, cytomegalovirus (CMV) has been associated with CRC in some publications, albeit not being a fully acknowledged oncovirus. Moreover, recent microbiome studies set increasing grounds for new hypotheses on bacteriophages as interesting additional modulators in CRC carcinogenesis and progression. The present Review summarizes how particular groups of viruses, including bacteriophages, affect cells and the cellular and microbial microenvironment, thereby putatively contributing to foster CRC. This could be achieved, for example, by promoting several processes – such as DNA damage, chromosomal instability, or molecular aspects of cell proliferation, CRC progression and metastasis – not necessarily by direct infection of epithelial cells only, but also by interaction with the microenvironment of infected cells. In this context, there are striking common features of EBV, CMV, HPV and JCV that are able to promote oncogenesis, in terms of establishing latent infections and affecting p53‐/pRb‐driven, epithelial–mesenchymal transition (EMT)‐/EGFR‐associated and especially Wnt/β‐catenin‐driven pathways. We speculate that, at least in part, such viral impacts on particular pathways might be reflected in lasting (e.g. mutational or further genomic) fingerprints of viruses in cells. Also, the complex interplay between several species within the intestinal microbiome, involving a direct or indirect impact on colorectal and microenvironmental cells but also between, for example, phages and bacterial and viral pathogens, and further novel species certainly might, in part, explain ongoing difficulties to establish unequivocal monocausal links between specific viral infections and CRC.

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Epstein-Barr virus stably confers an invasive phenotype to epithelial cells through reprogramming of the WNT pathway

Cited by 24 publications

References 79 publications

Inhibition of Epstein-Barr Virus Replication in Human Papillomavirus-Immortalized Keratinocytes

Inhibition of Epstein-Barr Virus Replication in Human Papillomavirus-Immortalized Keratinocytes

Metagenomic analysis of primary colorectal carcinomas and their metastases identifies potential microbial risk factors

Viruses in colorectal cancer

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