Possible contributing role of Epstein-Barr virus (EBV) as a cofactor in human papillomavirus (HPV)-associated cervical carcinogenesis

Aromseree, Sirinart; Pientong, Chamsai; Swangphon, Piyawut; Chaiwongkot, Arkom; Patarapadungkit, Natcha; Kleebkaow, Pilaiwan; Tungsiriwattana, Thumwadee; Kongyingyoes, Bunkerd; Vendrig, Tineke; Middeldorp, Jaap M.; Ekalaksananan, Tipaya

doi:10.1016/j.jcv.2015.10.015

Cited by 25 publications

(37 citation statements)

References 44 publications

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“…In cervical cancer, PCR detection of EBV DNA or RNA is found in more than 60% of invasive squamous cell carcinoma (Aromseree et al, 2015; Khenchouche et al, 2013; McCormick et al, 2015; Santos et al, 2009; Sasagawa et al, 2000). A correlation between the detection of EBV and lesion severity has also been observed, with EBV detected in 8–14% of normal samples, 12.5% of low grade CIN lesions, and 21–38% of high grade CIN lesions (Khenchouche et al, 2013).…”

Section: Hpv and Herpesvirusesmentioning

confidence: 99%

The interaction between human papillomavirus and other viruses

2017

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The etiological role of human papillomavirus (HPV) in anogenital tract and head and neck cancers is well established. However, only a low percentage of HPV-positive women develop cancer, indicating that HPV is necessary but not sufficient in carcinogenesis. Several biological and environmental cofactors have been implicated in the development of HPV-associated carcinoma that include immune status, hormonal changes, parity, dietary habits, tobacco usage, and co-infection with other sexually transmissible agents. Such cofactors likely contribute to HPV persistent infection through diverse mechanisms related to immune control, efficiency of HPV infection, and influences on tumor initiation and progression. Conversely, HPV co-infection with other factors may also harbor anti-tumor effects. Here, we review epidemiological and experimental studies investigating human immunodeficiency virus (HIV), herpes simplex virus (HSV) 1 and 2, human cytomegalovirus (HCMV), Epstein-Barr virus (EBV), BK virus (BKV) JC virus (JCV), and adeno-associated virus (AAV) as viral cofactors in or therapeutic factors against the development of genital and oral HPV-associated carcinomas.

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Section: Hpv and Herpesvirusesmentioning

confidence: 99%

The interaction between human papillomavirus and other viruses

2017

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“…The co-infection was associated with HPV episomal form. In- situ hybridization staining of EBERs in cervical tissues showed localization of EBV in the nuclei of infiltrating lymphocytes in stromal layers [6]. Thus, we hypothesized that EBV-infected B lymphocytes infiltrating cervical tissues may not be just a commensal agent but may play a role in manipulating the microenvironment and HPV-infected cells to induce the development of cervical cancer by secretion of their products via exosomes.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, a correlation between EBV infection and high-risk HPV types and HPV episomal form was found. Interestingly, we demonstrated that EBV localized in infiltrating leukocytes adjacent to tumor epithelium and we did not observe EBV infection in epithelial cells [6]. Thus, we hypothesized that HPV infection, which induces many inflammatory signals [7], recruits EBV-carrying B lymphocytes to the infected area.…”

Section: Introductionmentioning

confidence: 99%

High Levels of EBV-Encoded RNA 1 (EBER1) Trigger Interferon and Inflammation-Related Genes in Keratinocytes Expressing HPV16 E6/E7

et al. 2017

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Different types of cells infected with Epstein-Barr virus (EBV) can release exosomes containing viral components that functionally affect neighboring cells. Previously, we found that EBV was localized mostly in infiltrating lymphocytes within the stromal layer of cervical lesions. In this study, we aimed to determine effects of exosome-transferred EBV-encoded RNAs (EBERs) on keratinocytes expressing human papillomavirus (HPV) 16 E6/E7 (DonorI-HPV16 HFKs). Lipid transfection of in vitro-transcribed EBER1 molecules (ivt EBER1) into DonorI-HPV16 HFKs caused strong induction of interferon (IFN)-related genes and interleukin 6 (IL-6). To gain insights into the physiological situation, monocyte-derived dendritic cells (moDCs), low passage DonorI-HPV16 HFKs and primary keratinocytes were used as recipient cells for internalization of exosomes from wild-type EBV (wt EBV) or B95-8 EBV-infected lymphoblastoid cell lines (LCLs). qRT-PCR was used to determine the expression of EBER1, HPV16 E6/E7, IFN-related genes and IL-6 in recipient cells. The secretion of inflammatory cytokines was investigated using cytometric bead array. Wt EBV-modified exosomes induced both IFN-related genes and IL-6 upon uptake into moDCs, while exosomes from B95-8 EBV LCLs induced only IL-6 in moDCs. Internalization of EBV–modified exosomes was demonstrated in DonorI-HPV16 HFKs, yielding only EBER1 but not EBER2. However, EBER1 transferred by exosomes did not induce IFN-related genes or IL-6 expression and inflammatory cytokine secretion in DonorI-HPV16 HFKs and primary keratinocytes. EBER1 copy numbers in exosomes from wt EBV-infected LCLs were 10-fold higher than in exosomes from B95-8 LCLs (equal cell equivalent), whereas ivt EBER1 was used at approximately 100-fold higher concentration than in exosomes. These results demonstrated that the induction of IFN-related genes and IL-6 by EBER1 depends on quantity of EBER1 and type of recipient cells. High levels of EBER1 in cervical cells or infiltrating dendritic cells may play a role in the inflammation-to-oncogenesis transition of HPV-associated cervical cancer through modulation of innate immune signals.

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“…Advancing CIN disease severity, on the other hand, is related to increased diversity of vaginal microbiota and may promote HPV persistence and carcinogenesis [23]. Also, infiltrating lymphocytes infected with Epstein-Barr virus may play a role in cervical carcinogenesis related to episomal high-risk HPV [24].…”

Section: Regulatory Elementsmentioning

confidence: 99%

Dimensions of Cooperative Cervical Oncogenesis in Abortive Infection by Human Papillomavirus

Agius¹

2017

Gynecol Obstet

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Induced proliferation of Human Papillomavirus genome and proliferation of host basal and suprabasal epithelial cells in the transformation zone are inherently linked in vegetative production of progeny viral particles, as evidenced by the association of late L1 and L2 late elements that encode capsid proteins in the superficial squamous cells of the cervix. Abortive infection is a staged series of networks that utilize cytokine activities towards the utilization of susceptible breakage points within the host cell genome towards an integration series of mechanisms that promotes the immortalization of the epithelial cells principally by the E7 and the transformation by E6 action. Oncogenic transformation is further enhanced by cooperative activities of combined E6-E7 that possibly act as fusion oncoproteins. One intriguing question is the possible dysfunctionality of episomal partitioning of HPV DNA and persistence and integration of this in oncogenesis, emphasizing possible roles of E2 protein of HPV type-16 in transformation.

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Possible contributing role of Epstein-Barr virus (EBV) as a cofactor in human papillomavirus (HPV)-associated cervical carcinogenesis

Cited by 25 publications

References 44 publications

The interaction between human papillomavirus and other viruses

The interaction between human papillomavirus and other viruses

High Levels of EBV-Encoded RNA 1 (EBER1) Trigger Interferon and Inflammation-Related Genes in Keratinocytes Expressing HPV16 E6/E7

Dimensions of Cooperative Cervical Oncogenesis in Abortive Infection by Human Papillomavirus

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