The APOBEC3 genes and their role in cancer: insights from human papillomavirus

Smith, Nicola J.; Fenton, Tim R.

doi:10.1530/jme-19-0011

Cited by 38 publications

(36 citation statements)

References 156 publications

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“…Several viruses of these families are well-known tumor viruses (HPV-16, HPV-18, Merkel cell polyomavirus, etc.) and a mechanistic link between A3 expression and the development of cancer has been established in HPV positive cervical and oesopharyngeal cancers [75,76]. S12 Fig shows oncogenic viruses (confirmed or suspected) and their respective A3 footprint.…”

Section: Plos Pathogensmentioning

confidence: 99%

Footprint of the host restriction factors APOBEC3 on the genome of human viruses

et al. 2020

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APOBEC3 enzymes are innate immune effectors that introduce mutations into viral genomes. These enzymes are cytidine deaminases which transform cytosine into uracil. They preferentially mutate cytidine preceded by thymidine making the 5'TC motif their favored target. Viruses have evolved different strategies to evade APOBEC3 restriction. Certain viruses actively encode viral proteins antagonizing the APOBEC3s, others passively face the APOBEC3 selection pressure thanks to a depleted genome for APOBEC3-targeted motifs. Hence, the APOBEC3s left on the genome of certain viruses an evolutionary footprint. The aim of our study is the identification of these viruses having a genome shaped by the APOBEC3s. We analyzed the genome of 33,400 human viruses for the depletion of APO-BEC3-favored motifs. We demonstrate that the APOBEC3 selection pressure impacts at least 22% of all currently annotated human viral species. The papillomaviridae and polyomaviridae are the most intensively footprinted families; evidencing a selection pressure acting genome-wide and on both strands. Members of the parvoviridae family are differentially targeted in term of both magnitude and localization of the footprint. Interestingly, a massive APOBEC3 footprint is present on both strands of the B19 erythroparvovirus; making this viral genome one of the most cleaned sequences for APOBEC3-favored motifs. We also identified the endemic coronaviridae as significantly footprinted. Interestingly, no such footprint has been detected on the zoonotic MERS-CoV, SARS-CoV-1 and SARS-CoV-2 coronaviruses. In addition to viruses that are footprinted genome-wide, certain viruses are footprinted only on very short sections of their genome. That is the case for the gamma-herpesviridae and adenoviridae where the footprint is localized on the lytic origins of replication. A mild footprint can also be detected on the negative strand of the reverse transcribing HIV-1, HIV-2, HTLV-1 and HBV viruses. Together, our data illustrate the extent of the APOBEC3 selection pressure on the human viruses and identify new putatively APOBEC3-targeted viruses.

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Section: Plos Pathogensmentioning

confidence: 99%

Footprint of the host restriction factors APOBEC3 on the genome of human viruses

et al. 2020

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“…In innate immunity, the role of APOBEC3 genes in HPVrelated cancer is presumed to be an aberrant trigger and/or dysregulation that results in somatic mutation observed in cervical cancer (31). For the different mean expression patterns of APOBEC3 genes between the two LOXL2 clusters observed in our research and their negative correlation in the SiHa and HeLa cell lines, we tentatively put forward LOXL2 may be a trigger of APOBEC3 gene dysregulation in cervical cancer.…”

Section: Discussionmentioning

confidence: 56%

“…Previous studies have indicated that APOBEC3 family genes play a key role in innate immunity (28,29), HPV associated carcinogenesis (30), and development of chemoresistance in cancer (31,32). By clustering the 176 core-set samples into two groups, we found that the mean expression of APOBEC3 family genes was higher in the low-LOXL2 cluster (Figure 4A), including APOBEC3A (8.384 ± 0.2478 in low cluster vs. 6.80 ± 0.2578 in high cluster), APOBEC3B (9.904 ± 0.1226 in low cluster vs. 8.588 ± 0.2501 in high cluster), APOBEC3D (7.273 ± 0.1367 in low cluster vs. 6.547 ± 0.1360 in high cluster), APOBEC3F (7.988 ± 0.09133 in low cluster vs. 7.597 ± 0.08861 in high cluster), APOBEC3G (8.929 ± 0.1288 in low cluster vs. 8.333 ± 0.1326 in high cluster), and APOBEC3H (4.163 ± 0.1426 in low cluster vs. 3.617 ± 0.1237 in high cluster).…”

Section: Apobec3 Family Gene Expression Levels Were Negatively Correlmentioning

confidence: 99%

LOXL2 Expression Status Is Correlated With Molecular Characterizations of Cervical Carcinoma and Associated With Poor Cancer Survival via Epithelial-Mesenchymal Transition (EMT) Phenotype

et al. 2020

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As molecular analyses based on high-throughput sequencing have developed, the molecular classification of cancer has facilitated clinical work. The aim of the present study was to identify a new potential therapeutic target for cervical carcinoma by molecular analyses. We firstly tested the LOXL2 expression pattern in 50 paired normal cervix and cervical carcinoma via qPCR and immunohistochemistry, and the LOXL2 expression pattern was found to be in accordance with public datasets from Gene Expression Omnibus (GEO). Then, we comprehensively rewired the 176 cervical carcinoma samples from The Cancer Genome Atlas (TCGA), subsequently clustered the samples into two groups corresponding to LOXL2 expression to determined the associations between LOXL2 expression status and molecular characterizations of cervical carcinoma. In vitro assays for further verifying the correlations in SiHa-shLOXL2 and HeLa-shLOXL2 cell lines. In this study, we found that LOXL2 highly expressed in carcinoma tissue, with 14 CpG islands of LOXL2 promoter that were significantly and negatively associated with its expression in cervical carcinoma. And there were notable correlations among LOXL2 expression status and molecular characterizations of cervical carcinoma, including diagnostic age, HPV A7 types, mRNA molecular clusters, miRNA molecular clusters, and DNA methylation molecular clusters et al. In addition, high LOXL2 expression was negatively correlated with lower tumor mutation density, especially in EP300, ERBB2, EGFR and NOTCH2, and was negatively correlated with lower expression of APOBEC3 family genes, such as APOBEC3A, APOBEC3B, APOBEC3D, and APOBEC3G. Furthermore, high LOXL2 expression was associated with poor overall (OS) and poor disease-free survival (DFS) in cervical carcinoma, and was associated with higher epithelial-mesenchymal transition (EMT) score, enrichment of extracellular matrix (ECM) signaling, the phenotype that was found to be associated with poor prognosis Cao et al. LOXL2 With EMT in Cervical Carcinoma in cervical carcinoma from TCGA. Conversely, the ability of cell proliferation and cell migration were reversed in LOXL2 knock-down cervical cell lines via regulating the genes' expression of EMT phenotype in vitro. Overall, we demonstrated the correlation between LOXL2 expression status and cancer molecular characterizations of cervical carcinoma, and identified LOXL2 may serve as a therapeutic target for such carcinoma.

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“…The link between RNA editing and HPV viral replication is not new. Previous evidence showing upregulation of immune signaling pathways has been associated to the cytidine deaminase APOBEC derived modifications 31 , suggesting that epitranscriptomic changes induced modulate innate immunity affecting and affect HPV outcome. Contrary to results showing that modulation of innate immune response is a consequence of the direct modification of HPV genome by APOBEC or ADAR1 in the case of other infections 7 , we did not detect any ADAR1-mediated A-to-I editing in HPV16 transcripts, therefore indicating that it might be related to the role of ADAR1 as a regulator of innate immune activation or to alternative functions of ADAR1.…”

Section: Discussionmentioning

confidence: 97%

“…For HPV detection, the same samples were used to determine HPV genotype using the AnyplexTM II HPV28 real-time PCR (Seegene, Seoul, Korea) as described before 41 . HPV genotypes were classified as High (genotypes 16,18,31,33,35,39,45,51,52,56,58,59, 66 and 68) and low (6,11,40,42,43,44,54,61 and 70) oncogenic risk as described 41 .…”

Section: Human Cytokine Network Array Cytokine Expression Was Evaluamentioning

confidence: 99%

ADAR1 function affects HPV replication and is associated to recurrent human papillomavirus-induced dysplasia in HIV coinfected individuals

Pujantell¹,

Badía²,

Galván-Femenía³

et al. 2019

Sci Rep

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Infection by human papillomavirus (HPV) alters the microenvironment of keratinocytes as a mechanism to evade the immune system. A-to-I editing by ADAR1 has been reported to regulate innate immunity in response to viral infections. Here, we evaluated the role of ADAR1 in HPV infection in vitro and in vivo. Innate immune activation was characterized in human keratinocyte cell lines constitutively infected or not with HPV. ADAR1 knockdown induced an innate immune response through enhanced expression of RIG-I-like receptors (RLR) signaling cascade, over-production of type-I IFNs and pro-inflammatory cytokines. ADAR1 knockdown enhanced expression of HPV proteins, a process dependent on innate immune function as no A-to-I editing could be identified in HPV transcripts. A genetic association studywas performed in a cohort of HPV/HIV infected individuals followed for a median of 6 years (range 0.1-24). We identified the low frequency haplotype AACCAT significantly associated with recurrent HPV dysplasia, suggesting a role of ADAR1 in the outcome of HPV infection in HIV+ individuals. In summary, our results suggest that ADAR1-mediated innate immune activation may influence HPV disease outcome, therefore indicating that modification of innate immune effectors regulated by ADAR1 could be a therapeutic strategy against HPV infection.HPV is a small non-enveloped double-stranded DNA virus that infects keratinocytes. Most HPV infections clear spontaneously, however, persistent HPV infection is strongly associated with risk of several cancers including cervical, laryngeal, esophageal and anal cancer 1 . In immunosuppressed individuals there is a higher rate of cervical and anal HPV infections 2 . HPV infection favors HIV acquisition, and HIV-infected individuals encompass a heavier burden of HPV-induced dysplasia and cancer due to progressive immune suppression and impaired cell-mediated immunity. Persistent HPV infections are strong determinants of anal high-grade squamous intraepithelial lesions (HSIL) 3 .Innate immune responses are characterized by production of a complex network of cytokines that effectively activate cellular immune cells 4 . Pattern recognition receptors (PRRs) include the RNA-binding helicase family of RIG-I-like receptors (RLR: RIG-I and MDA5), and the family of Toll-like receptors (TLR). In response to viral infections, produced type I interferons (IFN) activate the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway, which, in turn, induces the expression of additional interferon signaling

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The APOBEC3 genes and their role in cancer: insights from human papillomavirus

Cited by 38 publications

References 156 publications

Footprint of the host restriction factors APOBEC3 on the genome of human viruses

Footprint of the host restriction factors APOBEC3 on the genome of human viruses

LOXL2 Expression Status Is Correlated With Molecular Characterizations of Cervical Carcinoma and Associated With Poor Cancer Survival via Epithelial-Mesenchymal Transition (EMT) Phenotype

ADAR1 function affects HPV replication and is associated to recurrent human papillomavirus-induced dysplasia in HIV coinfected individuals

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