The Role of E6 Spliced Isoforms (E6*) in Human Papillomavirus-Induced Carcinogenesis

Olmedo-Nieva, Leslie; Muñoz-Bello, J. Omar; Contreras‐Paredes, Adriana; Lizano, Marcela

doi:10.3390/v10010045

Cited by 55 publications

(68 citation statements)

References 118 publications

(180 reference statements)

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“…The unique characteristics of viral transcription are the initiation of transcription at more than one promoter site and polycistronic pre-mRNA, causing the expression of multiple RNAs with many open reading frames. In addition to this event, the splicing mechanism maintains the proteomic diversity and generates isoforms of viral proteins E2 [113] and E6 [114]. The isoform of E6, E6*I, is considered to have anti-tumorigenic effects-it abrogates E6-mediated p53 degradation and help in initiating apoptosis [115].…”

Section: The Role Of Human Papillomavirus In Oncogenesismentioning

confidence: 99%

Factors in Oncogenesis: Viral Infections in Ovarian Cancer

Wilczyński

Paradowska

2020

Cancers

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Ovarian cancer (OC) is one of the leading causes of cancer death in women, with high-grade serous ovarian cancer (HGSOC) being the most lethal gynecologic malignancy among women. This high fatality rate is the result of diagnosis of a high number of new cases when cancer implants have already spread. The poor prognosis is due to our inadequate understanding of the molecular mechanisms preceding ovarian malignancy. Knowledge about the site of origination has been improved recently by the discovery of tube intraepithelial cancer (TIC), but the potential risk factors are still obscure. Due to high tumoral heterogeneity in OC, the establishment of early stage biomarkers is still underway. Microbial infection may induce or result in chronic inflammatory infection and in the pathogenesis of cancers. Microbiome research has shed light on the relationships between the host and microbiota, as well as the direct roles of host pathogens in cancer development, progression, and drug efficacy. While controversial, the detection of viruses within ovarian malignancies and fallopian tube tissues suggests that these pathogens may play a role in the development of OC. Genomic and proteomic approaches have enhanced the methods for identifying candidates in early screening. This article summarizes the existing knowledge related to the molecular mechanisms that lead to tumorigenesis in the ovary, as well as the viruses detected in OC cases and how they may elevate this process.

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Section: The Role Of Human Papillomavirus In Oncogenesismentioning

confidence: 99%

Factors in Oncogenesis: Viral Infections in Ovarian Cancer

Wilczyński

Paradowska

2020

Cancers

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“…E6 oncoprotein contributes to malignant progression through targeting a set of cellular proteins [ 30 ]. A common feature of E6-E7 mRNA from HR-HPV is to produce small isoforms termed E6*, whose cellular functions are poorly understood [ 18 ]. It is proposed that HPV-18 E6*I antagonizes the effects of full-length E6 [ 31 ], while some studies show that E6* has proper E6-independent functions [ 32 , 33 , 34 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

“…In HPV-16, at least four isoforms of E6* (I–IV) have been identified, whereas in HPV-18, only one has been reported hitherto, termed E6*I [ 15 ]. Although these E6 small isoforms are highly expressed in premalignant lesions and cervical cancer biopsies [ 16 , 17 ], their functions are poorly understood [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

HPV-18 E6 Oncoprotein and Its Spliced Isoform E6*I Regulate the Wnt/β-Catenin Cell Signaling Pathway through the TCF-4 Transcriptional Factor

Muñoz-Bello

Olmedo-Nieva

Castro-Muñoz

et al. 2018

IJMS

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The Wnt/β-catenin signaling pathway regulates cell proliferation and differentiation and its aberrant activation in cervical cancer has been described. Persistent infection with high risk human papillomavirus (HR-HPV) is the most important factor for the development of this neoplasia, since E6 and E7 viral oncoproteins alter cellular processes, promoting cervical cancer development. A role of HPV-16 E6 in Wnt/β-catenin signaling has been proposed, although the participation of HPV-18 E6 has not been previously studied. The aim of this work was to investigate the participation of HPV-18 E6 and E6*I, in the regulation of the Wnt/β-catenin signaling pathway. Here, we show that E6 proteins up-regulate TCF-4 transcriptional activity and promote overexpression of Wnt target genes. In addition, it was demonstrated that E6 and E6*I bind to the TCF-4 (T cell factor 4) and β-catenin, impacting TCF-4 stabilization. We found that both E6 and E6*I proteins interact with the promoter of Sp5, in vitro and in vivo. Moreover, although differences in TCF-4 transcriptional activation were found among E6 intratype variants, no changes were observed in the levels of regulated genes. Furthermore, our data support that E6 proteins cooperate with β-catenin to promote cell proliferation.

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“…One of the splice variants, 226^409 (E6*I) (mRNA B in Figure 2 ), has been shown to serve as the major E7-producing mRNA [ 49 ]. The E6*I protein may also be produced in its own right, since it has been detected in the HPV16-infected CaSki cell line [ 50 ] and was shown to function as an antagonist of the full-length E6 protein [ 51 , 52 , 53 ], thereby contributing an antitumorigenic function [ 54 ]. Irrespective of the function of the E6*I protein, it is apparent that 226^409 splicing is an important splicing event since it appears to be required for production of the E7-producing mRNAs.…”

Section: Regulation Of Hpv16 Gene Expression Mediated By Interactimentioning

confidence: 99%

Role of Viral Ribonucleoproteins in Human Papillomavirus Type 16 Gene Expression

Kajitani

Schwartz

2020

Viruses

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Human papillomaviruses (HPVs) depend on the cellular RNA-processing machineries including alternative RNA splicing and polyadenylation to coordinate HPV gene expression. HPV RNA processing is controlled by cis-regulatory RNA elements and trans-regulatory factors since the HPV splice sites are suboptimal. The definition of HPV exons and introns may differ between individual HPV mRNA species and is complicated by the fact that many HPV protein-coding sequences overlap. The formation of HPV ribonucleoproteins consisting of HPV pre-mRNAs and multiple cellular RNA-binding proteins may result in the different outcomes of HPV gene expression, which contributes to the HPV life cycle progression and HPV-associated cancer development. In this review, we summarize the regulation of HPV16 gene expression at the level of RNA processing with focus on the interactions between HPV16 pre-mRNAs and cellular RNA-binding factors.

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The Role of E6 Spliced Isoforms (E6*) in Human Papillomavirus-Induced Carcinogenesis

Cited by 55 publications

References 118 publications

Factors in Oncogenesis: Viral Infections in Ovarian Cancer

Factors in Oncogenesis: Viral Infections in Ovarian Cancer

HPV-18 E6 Oncoprotein and Its Spliced Isoform E6*I Regulate the Wnt/β-Catenin Cell Signaling Pathway through the TCF-4 Transcriptional Factor

Role of Viral Ribonucleoproteins in Human Papillomavirus Type 16 Gene Expression

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