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Article ; Online: [Human Papillomavirus Carcinogenesis Mediated by APOBEC Mutagenesis].

Kukimoto, Iwao

Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan

2018 Volume 139, Issue 1, Page(s) 75–79

Abstract: Persistent infection with oncogenic human papillomaviruses (HPVs) is necessary for the development of cervical cancer, although the accumulation of somatic mutations in the host genome is also required for the generation of invasive cervical cancer. ... ...

Abstract	Persistent infection with oncogenic human papillomaviruses (HPVs) is necessary for the development of cervical cancer, although the accumulation of somatic mutations in the host genome is also required for the generation of invasive cervical cancer. Recent studies have demonstrated concomitant genetic changes in the HPV genome; however, their relevance to cervical carcinogenesis is poorly understood. Here we review our recent study investigating the within-host genetic diversity of HPV and its relationship with cervical cancer progression through deep sequencing analyses of viral whole-genome sequences in clinical specimens. Intriguingly, HPV genomes within individual clinical samples show an astonishingly high level of nucleotide variation across all histological grades of cervical lesions. Among the various substitution patterns, C-to-T and C-to-A substitutions are the predominant changes observed in the HPV genomes. Analysis of the trinucleotide context for substituted bases reveals that TpCpN (N is any nucleotide), which is a preferred target sequence for the cellular apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) proteins, is the major target for C-to-T substitutions in the HPV genomes. These mutational signature analyses strongly imply that within-host HPV variations are mostly generated through APOBEC-mediated mutagenesis. Because the HPV oncogenes E6 and E7 harbor APOBEC-related mutations, we propose a potential role for APOBEC-mediated mutagenesis in cervical carcinogenesis.
MeSH term(s)	APOBEC Deaminases/genetics ; Female ; Genetic Variation ; Genome, Viral/genetics ; Humans ; Mutation ; Nucleotides/genetics ; Papillomaviridae/genetics ; Papillomaviridae/pathogenicity ; Uterine Cervical Neoplasms/genetics ; Uterine Cervical Neoplasms/virology ; Whole Genome Sequencing
Chemical Substances	Nucleotides ; APOBEC Deaminases (EC 3.5.4.5)
Language	Japanese
Publishing date	2018-12-31
Publishing country	Japan
Document type	Journal Article ; Review
ZDB-ID	200514-1
ISSN	1347-5231 ; 0031-6903 ; 0372-7750 ; 0919-2085 ; 0919-2131
ISSN (online)	1347-5231
ISSN	0031-6903 ; 0372-7750 ; 0919-2085 ; 0919-2131
DOI	10.1248/yakushi.18-00164-3
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Article ; Online: A prospective clinical trial of diathermy ablation for patients with high-grade cervical intraepithelial neoplasia from a single institution in Japan.

Mitani, Takeji / Kukimoto, Iwao / Tsukamoto, Tetsuya / Nomura, Hiroyuki / Fujii, Takuma

Scientific reports

2024 Volume 14, Issue 1, Page(s) 2632

Abstract: Approximately 500,000 women are diagnosed with cervical cancer annually, with high-grade cervical intraepithelial neoplasia (CIN) estimated to be 20 times higher. The diathermy ablation is an inexpensive minimally invasive surgeries for CIN. However, ... ...

Abstract	Approximately 500,000 women are diagnosed with cervical cancer annually, with high-grade cervical intraepithelial neoplasia (CIN) estimated to be 20 times higher. The diathermy ablation is an inexpensive minimally invasive surgeries for CIN. However, little is known about the treatment outcomes. A prospective clinical trial was therefore conducted to evaluate ablation outcomes based on detailed colposcopy findings, cytology, and biopsy results over a two-year period. We enrolled CIN2 (n = 32) and CIN3 (n = 7) patients. Eligibility criteria included: aged between 29 and 49 (median: 36, mean: 36.3), visible transformation zone with high-grade lesions not entirely occupying the cervix, and histologically diagnosed with CIN2 or CIN3. Cytology and HPV genotyping were performed, and colposcopic findings were evaluated. Colposcopy-guided diathermy ablation was conducted by a certified gynecologic oncologist. The incidence of recurrent or residual disease was 5.1% (2/39, 95% confidence interval: - 0.02 to 0.12). The prevalence of HPV infection at 12 months decreased after surgery, as 67.6% (23/34, 0.52-0.83) of patients were HPV-negative. No severe adverse events were reported, while there were five pregnancies with full-term deliveries. The promising outcome was possibly due to selection of rigorous surgical indication and skilled surgical techniques. The study highlights the importance of experienced and skilled colposcopists.TrialRegistry This study was registered in the clinical trial registration system of the University hospital Medical Information Network Clinical Trials Registry (UMIN-CTR ID: UMIN000024483). Open for the trial to the public through the website: 01/11/2016. First registration of the patient: 30/01/2017.
MeSH term(s)	Pregnancy ; Humans ; Female ; Adult ; Middle Aged ; Papillomavirus Infections ; Japan/epidemiology ; Prospective Studies ; Uterine Cervical Dysplasia/pathology ; Uterine Cervical Neoplasms/pathology ; Diathermy ; Papillomaviridae
Language	English
Publishing date	2024-02-01
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-024-53197-8
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Article ; Online: Correction for Mori et al., "Nuclear proinflammatory cytokine S100A9 enhances expression of human papillomavirus oncogenes via transcription factor TEAD1".

Mori, Seiichiro / Ishii, Yoshiyuki / Takeuchi, Takamasa / Kukimoto, Iwao

Journal of virology

2023 Volume 97, Issue 11, Page(s) e0149923

Language	English
Publishing date	2023-10-26
Publishing country	United States
Document type	Journal Article ; Published Erratum
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/jvi.01499-23
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Article ; Online: Nuclear proinflammatory cytokine S100A9 enhances expression of human papillomavirus oncogenes via transcription factor TEAD1.

Mori, Seiichiro / Ishii, Yoshiyuki / Takeuchi, Takamasa / Kukimoto, Iwao

Journal of virology

2023 Volume 97, Issue 8, Page(s) e0081523

Abstract: Transcription of the human papillomavirus (HPV) oncogenes, ...

Abstract	Transcription of the human papillomavirus (HPV) oncogenes,
MeSH term(s)	Female ; Humans ; Carcinogenesis/genetics ; Human Papillomavirus Viruses ; Oncogene Proteins, Viral/genetics ; Papillomavirus E7 Proteins/genetics ; Papillomavirus Infections/genetics ; Proteomics ; TEA Domain Transcription Factors/genetics ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Uterine Cervical Neoplasms/genetics ; Uterine Cervical Neoplasms/virology ; Calgranulin B/genetics
Chemical Substances	Oncogene Proteins, Viral ; Papillomavirus E7 Proteins ; TEA Domain Transcription Factors ; TEAD1 protein, human ; Transcription Factors ; S100A9 protein, human ; Calgranulin B
Language	English
Publishing date	2023-08-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/jvi.00815-23
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Article ; Online: Folliculin Prevents Lysosomal Degradation of Human Papillomavirus To Support Infectious Cell Entry.

Ishii, Yoshiyuki / Yamaji, Toshiyuki / Sekizuka, Tsuyoshi / Homma, Yuta / Mori, Seiichiro / Takeuchi, Takamasa / Kukimoto, Iwao

Journal of virology

2023 Volume 97, Issue 5, Page(s) e0005623

Abstract: Human papillomavirus (HPV) infects epithelial basal cells in the mucosa and either proliferates with the differentiation of the basal cells or persists in them. Multiple host factors are required to support the HPV life cycle; however, the molecular ... ...

Abstract	Human papillomavirus (HPV) infects epithelial basal cells in the mucosa and either proliferates with the differentiation of the basal cells or persists in them. Multiple host factors are required to support the HPV life cycle; however, the molecular mechanisms involved in cell entry are not yet fully understood. In this study, we performed a genome-wide clustered regularly interspaced short palindromic repeat (CRISPR)-CRISPR-associated protein 9 (Cas9) knockout (KO) screen in HeLa cells and identified folliculin (FLCN), a GTPase-activating protein for Rag GTPases, as an important host factor for HPV infection. The introduction of single guide RNAs for the
MeSH term(s)	Humans ; GTPase-Activating Proteins ; HeLa Cells ; Human Papillomavirus Viruses/physiology ; Lysosomes/metabolism ; Papillomavirus Infections ; Virus Internalization ; Tumor Suppressor Proteins/metabolism ; Proto-Oncogene Proteins/metabolism
Chemical Substances	GTPase-Activating Proteins ; FLCN protein, human ; Tumor Suppressor Proteins ; Proto-Oncogene Proteins
Language	English
Publishing date	2023-05-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/jvi.00056-23
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Article ; Online: Intra-Patient Genomic Variations of Human Papillomavirus Type 31 in Cervical Cancer and Precancer.

Kogure, Gota / Tanaka, Kohsei / Matsui, Tomoya / Onuki, Mamiko / Matsumoto, Koji / Iwata, Takashi / Kukimoto, Iwao

Viruses

2023 Volume 15, Issue 10

Abstract: Human papillomavirus type 31 (HPV31) is detected less frequently in cervical cancer than two major causative types, HPV16 and HPV18. Here, we report a comprehensive analysis of HPV31 genome sequences in cervical lesions collected from Japanese women. Of ... ...

Abstract	Human papillomavirus type 31 (HPV31) is detected less frequently in cervical cancer than two major causative types, HPV16 and HPV18. Here, we report a comprehensive analysis of HPV31 genome sequences in cervical lesions collected from Japanese women. Of 52 HPV31-positive cervical specimens analyzed by deep sequencing, 43 samples yielded complete genome sequences of around 7900 base pairs and 9 samples yielded partially deleted genome sequences. Phylogenetic analysis showed that HPV31 variant distribution was lineage A in 19 samples (36.5%), lineage B in 28 samples (53.8%), and lineage C in 5 samples (9.6%), indicating that lineage B variants are dominant among HPV31 infections in Japan. Deletions in the viral genome were found in the region from the
MeSH term(s)	Female ; Humans ; Uterine Cervical Neoplasms ; Phylogeny ; Human Papillomavirus Viruses ; Human papillomavirus 31/genetics ; Uterine Cervical Dysplasia ; Genome, Viral ; Genomics ; Papillomavirus Infections ; Oncogene Proteins, Viral/genetics ; Genetic Variation ; Papillomavirus E7 Proteins/genetics
Chemical Substances	Oncogene Proteins, Viral ; Papillomavirus E7 Proteins
Language	English
Publishing date	2023-10-17
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v15102104
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Article: Ancient Evolutionary History of Human Papillomavirus Type 16, 18 and 58 Variants Prevalent Exclusively in Japan

Tanaka, Kohsei / Kogure, Gota / Onuki, Mamiko / Matsumoto, Koji / Iwata, Takashi / Aoki, Daisuke / Kukimoto, Iwao

Viruses. 2022 Feb. 24, v. 14, no. 3

2022

Abstract: Human papillomavirus (HPV) is a sexually transmitted virus with an approximately 8-kilo base DNA genome, which establishes long-term persistent infection in anogenital tissues. High levels of genetic variations, including viral genotypes and intra-type ... ...

Abstract	Human papillomavirus (HPV) is a sexually transmitted virus with an approximately 8-kilo base DNA genome, which establishes long-term persistent infection in anogenital tissues. High levels of genetic variations, including viral genotypes and intra-type variants, have been described for HPV genomes, together with geographical differences in the distribution of genotypes and variants. Here, by employing a maximum likelihood method, we performed phylogenetic analyses of the complete genome sequences of HPV16, HPV18 and HPV58 available from GenBank (n = 627, 146 and 157, respectively). We found several characteristic clusters that exclusively contain HPV genomes from Japan: two for HPV16 (sublineages A4 and A5), one for HPV18 (sublineage A1) and two for HPV58 (sublineages A1 and A2). Bayesian phylogenetic analyses of concatenated viral gene sequences showed that divergence of the most recent common ancestor of these Japan-specific clades was estimated to have occurred ~98,000 years before present (YBP) for HPV16 A4, ~39,000 YBP for HPV16 A5, ~38,000 YBP for HPV18 A1, ~26,000 for HPV58 A1 and ~25,000 YBP for HPV58 A2. This estimated timeframe for the divergence of the Japan-specific clades suggests that the introduction of these HPV variants into the Japanese archipelago dates back to at least ~25,000 YBP and provides a scenario of virus co-migration with ancestral Japanese populations from continental Asia during the Upper Paleolithic period.
Keywords	DNA ; Human papillomavirus type 16 ; Japan ; ancestry ; chronic diseases ; genes ; humans ; phylogeny ; statistical analysis ; viruses
Language	English
Dates of publication	2022-0224
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2516098-9
ISSN	1999-4915
ISSN	1999-4915
DOI	10.3390/v14030464
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: The Transcriptional Cofactor VGLL1 Drives Transcription of Human Papillomavirus Early Genes via TEAD1.

Mori, Seiichiro / Takeuchi, Takamasa / Ishii, Yoshiyuki / Kukimoto, Iwao

Journal of virology

2020 Volume 94, Issue 10

Abstract: The TEAD family of transcription factors requires associating cofactors to induce gene expression. TEAD1 is known to activate the early promoter of human papillomavirus (HPV), but the precise mechanisms of TEAD1-mediated transactivation of the HPV ... ...

Abstract	The TEAD family of transcription factors requires associating cofactors to induce gene expression. TEAD1 is known to activate the early promoter of human papillomavirus (HPV), but the precise mechanisms of TEAD1-mediated transactivation of the HPV promoter, including its relevant cofactors, remain unexplored. Here, we reveal that VGLL1, a TEAD-interacting cofactor, contributes to HPV early gene expression. Knockdown of VGLL1 and/or TEAD1 led to a decrease in viral early gene expression in human cervical keratinocytes and cervical cancer cell lines. We identified 11 TEAD1 target sites in the HPV16 long control region (LCR) by
MeSH term(s)	Cell Line ; Cervix Uteri ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Epithelium ; Female ; Gene Expression Regulation, Viral ; Gene Knockdown Techniques ; Human papillomavirus 16/genetics ; Human papillomavirus 16/physiology ; Humans ; Keratinocytes/virology ; Muscle Proteins/metabolism ; Nuclear Proteins/metabolism ; Papillomaviridae/genetics ; Papillomaviridae/physiology ; Papillomavirus Infections/genetics ; Papillomavirus Infections/metabolism ; Promoter Regions, Genetic ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Transcription, Genetic ; Transcriptional Activation ; Transcriptome ; Up-Regulation ; Uterine Cervical Neoplasms/virology
Chemical Substances	DNA-Binding Proteins ; Muscle Proteins ; Nuclear Proteins ; TEAD1 protein, human ; TEAD4 protein, human ; Transcription Factors ; VGLL1 protein, human
Language	English
Publishing date	2020-05-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.01945-19
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Article: The homeobox transcription factor HOXC13 upregulates human papillomavirus E1 gene expression and contributes to viral genome maintenance

Ishii, Yoshiyuki / Taguchi, Ayumi / Kukimoto, Iwao

FEBS letters. 2020 Feb., v. 594, no. 4

2020

Abstract: Human papillomavirus (HPV) infects the basal cells of epithelia and maintains its genome stably as episomes. However, the mechanisms of viral genome maintenance are not fully understood. Here, using normal human immortalized keratinocytes (NIKS), we ... ...

Abstract	Human papillomavirus (HPV) infects the basal cells of epithelia and maintains its genome stably as episomes. However, the mechanisms of viral genome maintenance are not fully understood. Here, using normal human immortalized keratinocytes (NIKS), we identified the homeobox transcription factor HOXC13 as a critical host factor for retaining the copy number of HPV genomes in the cell. HOXC13 knockdown in NIKS significantly decreased mRNA levels of the E1 gene, which encodes a DNA helicase required for HPV genome replication, accompanied by a reduction of the viral genome copy number. Chromatin immunoprecipitation assays revealed HOXC13 binding to the long control region that regulates E1 expression. These results indicate that HOXC13 plays invaluable roles in maintaining HPV persistent infection through E1 gene upregulation.
Keywords	DNA helicases ; Papillomaviridae ; chromatin immunoprecipitation ; chronic diseases ; gene expression ; genes ; humans ; keratinocytes ; plasmids ; transcription factors ; viral genome
Language	English
Dates of publication	2020-02
Size	p. 751-762.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	JOURNAL ARTICLE
ZDB-ID	212746-5
ISSN	1873-3468 ; 0014-5793
ISSN (online)	1873-3468
ISSN	0014-5793
DOI	10.1002/1873-3468.13646
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Ancient Evolutionary History of Human Papillomavirus Type 16, 18 and 58 Variants Prevalent Exclusively in Japan.

Tanaka, Kohsei / Kogure, Gota / Onuki, Mamiko / Matsumoto, Koji / Iwata, Takashi / Aoki, Daisuke / Kukimoto, Iwao

Viruses

2022 Volume 14, Issue 3

Abstract	Human papillomavirus (HPV) is a sexually transmitted virus with an approximately 8-kilo base DNA genome, which establishes long-term persistent infection in anogenital tissues. High levels of genetic variations, including viral genotypes and intra-type variants, have been described for HPV genomes, together with geographical differences in the distribution of genotypes and variants. Here, by employing a maximum likelihood method, we performed phylogenetic analyses of the complete genome sequences of HPV16, HPV18 and HPV58 available from GenBank (
MeSH term(s)	Alphapapillomavirus/genetics ; Bayes Theorem ; Female ; Genetic Variation ; Genotype ; Human papillomavirus 16/genetics ; Humans ; Japan/epidemiology ; Papillomaviridae/genetics ; Papillomavirus Infections/epidemiology ; Phylogeny ; Uterine Cervical Neoplasms
Language	English
Publishing date	2022-02-24
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v14030464
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