The exon junction complex core factor eIF4A3 is a key regulator of HPV16 gene expression

Meznad, Koceila; Paget-Bailly, Philippe; Jacquin, Élise; Peigney, Anne; Aubin, F.; Guittaut, Michaël; Mougin, Christiane; Prétet, Jean‐Luc; Baguet, Aurélie

doi:10.1042/bsr20203488

Cited by 7 publications

(2 citation statements)

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“…Studies show that eIF2 counteracts viral infections, and phosphorylation of eIF2α leads to the inhibition of HPV18 E6 protein synthesis [ 17 ]. The eukaryotic translation initiation factors (EIFs) seem to be of importance in HPV infection and in the pathogenesis of different cancer forms including cervical cancer [ 18 , 19 , 20 , 21 , 22 , 23 ]. Besides eIF2α, EHBP1 is of particular interest among our identified proteins.…”

Section: Discussionmentioning

confidence: 99%

Changes in the Proteome in the Development of Chronic Human Papillomavirus Infection—A Prospective Study in HIV Positive and HIV Negative Rwandan Women

Bienvenu

Mukanyangezi

Rulisa

et al. 2021

Cancers

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Background: Effects on the proteome when a high risk (HR)-HPV infection occurs, when it is cleared and when it becomes chronic were investigated. Moreover, biomarker panels that could identify cervical risk lesions were assessed. Methods: Cytology, HPV screening and proteomics were performed on cervical samples from Rwandan HIV+ and HIV- women at baseline, at 9 months, at 18 months and at 24 months. Biological pathways were identified using the String database. Results: The most significantly affected pathway when an incident HR-HPV infection occurred was neutrophil degranulation, and vesicle-mediated transport was the most significantly affected pathway when an HR-HPV infection was cleared; protein insertion into membrane in chronic HR-HPV lesions and in lesions where HR-HPVs were cleared were compared; and cellular catabolic process in high-grade lesions was compared to that in negative lesions. A four-biomarker panel (EIF1; BLOC1S5; LIMCH1; SGTA) was identified, which was able to distinguish chronic HR-HPV lesions from cleared HR-HPV/negative lesions (sensitivity 100% and specificity 91%). Another four-biomarker panel (ERH; IGKV2-30; TMEM97; DNAJA4) was identified, which was able to distinguish high-grade lesions from low-grade/negative lesions (sensitivity 100% and specificity 81%). Conclusions: We have identified the biological pathways triggered in HR-HPV infection, when HR-HPV becomes chronic and when cervical risk lesions develop. Moreover, we have identified potential biomarkers that may help to identify women with cervical risk lesions.

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Section: Discussionmentioning

confidence: 99%

Changes in the Proteome in the Development of Chronic Human Papillomavirus Infection—A Prospective Study in HIV Positive and HIV Negative Rwandan Women

Bienvenu

Mukanyangezi

Rulisa

et al. 2021

Cancers

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“…The human papillomavirus (HPV) is a small (8,000 bp), non-enveloped double stranded circular DNA virus ( Pan et al, 2021 ; Sun et al, 2021 ; Wang et al, 2022 ). Persistent infection with HR-HPVs is highly related with various cancers, including cervical cancer (99.7%), head and neck squamous cell carcinomas (60%), anal cancer (93%), vulvar cancer (69%), vaginal cancer (75%), and penile cancers (47%) ( Yang et al, 2019 ; Meznad et al, 2021 ). As the most prevalent HR-HPV, HPV16 accounts for approximately 50% of cervical cancer cases ( Qmichou et al, 2013 ), its genome is composed of 6 early genes (E6, E7, E1, E2, E4, and E5) and 2 late genes (L1 and L2) ( Zhu et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

A replicative recombinant HPV16 E7 expression virus upregulates CD36 in C33A cells

Shao,

Wang,

Zheng

et al. 2023

Front. Microbiol.

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ObjectiveIn past decades, the role of high-risk HPV (HR-HPV) infection in cancer pathogenesis has been extensively studied. The viral E7 protein expressed in pre-malignant cells has been identified as an ideal target for immunological intervention. However, the cultivation of HPV in vitro remains a significant challenge, as well as the lack of methods for expressing the HPV E7 protein and generating replication-competent recombinant viral particles, which posed a major obstacle to further exploration of the function and carcinogenic mechanisms of the E7 oncoprotein. Therefore, it is imperative to investigate novel methodologies to construct replication-competent recombinant viral particles that express the HPV E7 protein to facilitate the study of its function.MethodsWe initiated the construction of recombinant viral particles by utilizing the ccdB-Kan forward/reverse screening system in conjunction with the Red/ExoCET recombinant system. We followed the infection of C33A cells with the obtained recombinant virus to enable the continuous expression of HPV16 E7. Afterwards, the total RNA was extracted and performed transcriptome sequencing using RNA-Seq technology to identify differentially expressed genes associated with HPV-induced oncogenicity.ResultsWe successfully established replicative recombinant viral particles expressing HPV16 E7 stably and continuously. The C33A cells were infected with recombinant viral particles to achieve overexpression of the E7 protein. Subsequently, RNA-Seq analysis was conducted to assess the changes in host cell gene expression. The results revealed an upregulation of the CD36 gene, which is associated with the HPV-induced oncogenic pathways, including PI3K-Akt and p53 signaling pathway. qRT-PCR analysis further identified that the upregulation of the CD36 gene due to the expression of HPV16 E7.ConclusionThe successful expression of HPV16 E7 in cells demonstrates that the replicated recombinant virus retains the replication and infection abilities of Ad4, while also upregulating the CD36 gene involved in the PI3K-Akt signaling and p53 pathways, thereby promoting cell proliferation. The outcome of this study provides a novel perspective and serves as a solid foundation for further exploration of HPV-related carcinogenesis and the development of replicative HPV recombinant vaccines capable of inducing protective immunity against HPV.

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The level of expression of HPV16 early transcripts is not associated with the natural history of cervical lesions

Jacquin,

Saunier,

Lepiller

et al. 2024

Journal of Medical Virology

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The natural history of cervical cancer is closely linked to that of high‐risk human papillomaviruses (HPV) infection. It is recognized that upon HPV DNA integration, partial or complete loss of the E2 open reading frame precludes expression of the corresponding protein, resulting in upregulation of the E6 and E7 viral oncoproteins. To better characterize HPV16 infection at the cervical level, viral load, viral DNA integration, and viral early transcript expression (E2, E5, and E6) were analyzed in a series of 158 cervical specimens representative of the full spectrum of cervical disease. Overall, the frequency of early transcript detection varied from 45% to 90% and tended to increase with lesion severity. In addition, the levels of E2, E5, and E6 transcript expression were slightly higher in high‐grade lesions than in cervical specimens without abnormalities. Notably, early transcript expression was clearly associated with viral load, and no inverse correlation was found between the expression of E2 and E6 transcripts. No clear association was found between early transcript expression and HPV16 DNA integration, with the exception that samples with a fully integrated HPV16 genome did not harbor E2 or E5 transcripts. In conclusion, early HPV16 transcript expression appears to be associated with viral load rather than lesion grade. From a practical point of view, quantification of HPV16 early transcripts is difficult to translate into a relevant biomarker for cervical cancer screening.

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The exon junction complex core factor eIF4A3 is a key regulator of HPV16 gene expression

Cited by 7 publications

References 64 publications

Changes in the Proteome in the Development of Chronic Human Papillomavirus Infection—A Prospective Study in HIV Positive and HIV Negative Rwandan Women

Changes in the Proteome in the Development of Chronic Human Papillomavirus Infection—A Prospective Study in HIV Positive and HIV Negative Rwandan Women

A replicative recombinant HPV16 E7 expression virus upregulates CD36 in C33A cells

The level of expression of HPV16 early transcripts is not associated with the natural history of cervical lesions

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