In Vivo and In Vitro Studies Suggest a Possible Involvement of HPV Infection in the Early Stage of Breast Carcinogenesis via APOBEC3B Induction

Ohba, Kenji; Ichiyama, Koji; Yajima, Misako; Gemma, Nobuhiro; Nikaido, Masaru; Wu, Qimeng; Chong, Pei Pei; Mori, Shuji; Yamamoto, Rain; Wong, John; Yamamoto, Naoki

doi:10.1371/journal.pone.0097787

Cited by 87 publications

(100 citation statements)

References 52 publications

(60 reference statements)

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“…1A). Previous studies reported that A3B expression was upregulated by HBV16 E6/E7 Ohba et al, 2014;Vieira et al, 2014). However, the HPV16-positive specimen used in this study expressed low levels of A3B (Fig.…”

Section: Expression Of Apobec3s In Healthy and Hpv16-positive Cervicamentioning

confidence: 48%

Detection of hypermutated human papillomavirus type 16 genome by Next-Generation Sequencing

et al. 2015

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Human papillomavirus type 16 (HPV16) is a major cause of cervical cancer. We previously demonstrated that C-to-T and G-to-A hypermutations accumulated in the HPV16 genome by APOBEC3 expression in vitro. To investigate in vivo characteristics of hypermutation, differential DNA denaturation-PCR (3D-PCR) was performed using three clinical specimens obtained from HPV16-positive cervical dysplasia, and detected hypermutation from two out of three specimens. One sample accumulating hypermutations in both E2 and the long control region (LCR) was further subjected to Next-Generation Sequencing, revealing that hypermutations spread across the LCR and all early genes. Notably, hypermutation was more frequently observed in the LCR, which contains a viral replication origin and the early promoter. APOBEC3 expressed abundantly in an HPV16-positive cervix, suggesting that single-stranded DNA exposed during viral replication and transcription may be efficient targets for deamination. The results further strengthen a role of APOBEC3 in introducing HPV16 hypermutation in vivo.

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Section: Expression Of Apobec3s In Healthy and Hpv16-positive Cervicamentioning

confidence: 48%

Detection of hypermutated human papillomavirus type 16 genome by Next-Generation Sequencing

et al. 2015

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“…B-Myb has been implicated in a positive regulatory role for Cdk1 expression (49,56). We and others have shown that E7 upregulates B-Myb expression (7,46). Moreover, downregulation of B-Myb-induced G 1 arrest in E7-expressing cells upon DNA damage has been described previously (59).…”

Section: Gene Expression Profiling Of Hpv-16 E7-expressing Cellsmentioning

confidence: 62%

“…Among these genes, the APOBEC-3B gene, a member of the cytidine deaminase gene family, is activated by HPV infection and increases genome instability (46). The nuclear protein DEK has shown to be upregulated in E7-expressing cells as well as cervical intraepithelial neoplasia (CIN) and cervical cancers.…”

Section: Gene Expression Profiling Of Hpv-16 E7-expressing Cellsmentioning

confidence: 99%

Role of WDHD1 in Human Papillomavirus-Mediated Oncogenesis Identified by Transcriptional Profiling of E7-Expressing Cells

Yang

Zhang

Gao

et al. 2016

J Virol

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The E7 oncoprotein of the high-risk human papillomavirus (HPV) plays a major role in HPV-induced carcinogenesis. E7 abrogates the G 1 cell cycle checkpoint and induces genomic instability, but the mechanism is not fully understood. In this study, we performed RNA sequencing (RNA-seq) to characterize the transcriptional profile of keratinocytes expressing HPV 16 (HPV-16) E7. At the transcriptome level, 236 genes were differentially expressed between E7 and vector control cells. A subset of the differentially expressed genes, most of them novel to E7-expressing cells, was further confirmed by real-time PCR. Of interest, the activities of multiple transcription factors were altered in E7-expressing cells. Through bioinformatics analysis, pathways altered in E7-expressing cells were investigated. The upregulated genes were enriched in cell cycle and DNA replication, as well as in the DNA metabolic process, transcription, DNA damage, DNA repair, and nucleotide metabolism. Specifically, we focused our studies on the gene encoding WDHD1 (WD repeat and high mobility group [HMG]-box DNA-binding protein), one of the genes that was upregulated in E7-expressing cells. WDHD1 is a component of the replisome that regulates DNA replication. Recent studies suggest that WDHD1 may also function as a DNA replication initiation factor as well as a G 1 checkpoint regulator. We found that in E7-expressing cells, the steady-state level of WDHD1 protein was increased along with the half-life. Moreover, downregulation of WDHD1 reduced E7-induced G 1 checkpoint abrogation and rereplication, demonstrating a novel function for WDHD1. These studies shed light on mechanisms by which HPV induces genomic instability and have therapeutic implications. IMPORTANCEThe high-risk HPV types induce cervical cancer and encode an E7 oncoprotein that plays a major role in HPV-induced carcinogenesis. However, the mechanism by which E7 induces carcinogenesis is not fully understood; specific anti-HPV agents are not available. In this study, we performed RNA-seq to characterize transcriptional profiling of keratinocytes expressing HPV-16 E7 and identified more than 200 genes that were differentially expressed between E7 and vector control cells. Through bioinformatics analysis, pathways altered in E7-expressing cells were identified. Significantly, the WDHD1 gene, one of the genes that is upregulated in E7-expressing cells, was found to play an important role in E7-induced G 1 checkpoint abrogation and rereplication. These studies shed light on mechanisms by which HPV induces genomic instability and have therapeutic implications. H uman papillomaviruses (HPVs) are small DNA viruses that replicate in squamous epithelia. Specific types of HPV (highrisk HPVs) are the causative agents for cervical and several other cancers (1). The transforming properties of high-risk HPVs such as HPV 16 (HPV-16) primarily depend on E7 as well as E6 oncogenes (1, 2). HPV E6 and E7 proteins promote the degradation of p53 and pRb, respectively (3, 4). E7 from the high-risk...

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“…Ohba et al showed that HPV E6 and E7 individually activate the A3B promoter and the E6/E7-induced DNA double-stranded breaks are abolished by A3B knockdown [7]. This suggests that the mutagenic activities of E6/E7 are attributable to the induction of A3B expression.…”

Section: Introductonmentioning

confidence: 99%

Identification of APOBEC3B promoter elements responsible for activation by human papillomavirus type 16 E6

Mori

Takeuchi

Ishii

et al. 2015

Biochemical and Biophysical Research Communications

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In Vivo and In Vitro Studies Suggest a Possible Involvement of HPV Infection in the Early Stage of Breast Carcinogenesis via APOBEC3B Induction

Cited by 87 publications

References 52 publications

Detection of hypermutated human papillomavirus type 16 genome by Next-Generation Sequencing

Detection of hypermutated human papillomavirus type 16 genome by Next-Generation Sequencing

Role of WDHD1 in Human Papillomavirus-Mediated Oncogenesis Identified by Transcriptional Profiling of E7-Expressing Cells

Identification of APOBEC3B promoter elements responsible for activation by human papillomavirus type 16 E6

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