Integration of the HPV16 genome does not invariably result in high levels of viral oncogene transcripts

Häfner, Norman; Driesch, Corina; Gajda, Mieczysław; Jansen, Lars; Kirchmayr, Richard; Runnebaum, Ingo B.; Dürst, Matthias

doi:10.1038/sj.onc.1210791

Cited by 112 publications

(100 citation statements)

References 39 publications

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“…Referring to a potential function of alternative splicing, however, examination of clinical samples has shown that the prevalence of the E6* mRNA isoform apparently increases with lesion severity, being finally the most abundant viral transcript found in cervical cancer cells and cell lines derived there from (10,25).…”

Section: Discussionmentioning

confidence: 99%

“…In a second selection step, cells with preferential E6 exon exclusion and high E7 expression gain a selective growth advantage during pro-gression (40), providing a reliable explanation for the prevalence of E6* mRNA found in most cervix carcinoma cell lines and CIN lesions (10,25). Analyzing the E6*/E6 ratio in two well-established HPV16 positive cervical carcinoma cells, both expressing mainly E6*, only SiHa cells showed a moderate isoform shift toward fulllength E6 after EGF addition, whereas CaSki cells were not responding (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Alternative splicing of human papillomavirus type-16 E6/E6* early mRNA is coupled to EGF signaling via Erk1/2 activation

Rosenberger

Arce

Langbein

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Certain types of human papillomaviruses (HPVs) are etiologically linked to cervical cancer. Their transforming capacity is encoded by a polycistronic premRNA, where alternative splicing leads to the translation of functional distinct proteins such as E6, E6*, and E7. Here we show that splicing of HPV16 E6/E7 ORF cassette is regulated by the epidermal growth factor (EGF) pathway. The presence of EGF was coupled to preferential E6 expression, whereas depletion of EGF, or treatment with EGF receptor (EGFR) neutralizing antibodies or the EGFR inhibitor tyrphostin AG1478, resulted in E6 exon exclusion in favor of E6*. As a consequence, increased p53 levels and enhanced translation of E7 with a subsequent reduction of the retinoblastoma protein pRb could be discerned. E6 exon exclusion upon EGF depletion was independent from promoter usage, mRNA stability, or selective mRNA transport. Time-course experiments and incubation with cycloheximide demonstrated that E6 alternative splicing is a direct and reversible effect of EGF signal transduction, not depending on de novo protein synthesis. Within this process, Erk1/2-kinase activation was the critical event for E6 exon inclusion, mediated by the upstream MAP kinase MEK1/2. Moreover, siRNA knockdown experiments revealed an involvement of splicing factors hnRNPA1 and hnRNPA2 in E6 exon exclusion, whereas the splicing factors Brm and Sam68 were found to promote E6 exon inclusion. Because there is a natural gradient of EGF and EGF receptor expression in the stratified epithelium, it is reasonable to assume that EGF modulates E6/E7 splicing during the viral life cycle and transformation.P articular types of human papillomaviruses (HPVs) such as HPV16, 18, 31, and 33, respectively, are the etiological agents for the development of anogenital tumors. Their transforming potential is encoded by the viral oncoproteins E6 and E7, where among other functions, E6 labilizes p53 and prevents apoptosis, and E7 promotes cell cycle progression by degrading the retinoblastoma protein pRb (1). HPV gene transcription is regulated by two main promoters, the early p97 and the late p670 promoter (2). Activation of either promoter is regulated by differentiation, resulting in the synthesis of polycistronic mRNAs, which are further regulated by differential splicing (3, 4). For polycistronic mRNAs, it is known that only the first ORF is translated efficiently when intercistronic distances are short (5).Alternative splicing can be regulated dependent on the developmental stage or by extracellular stimuli, where an increasing number of pathways and splicing factors have been identified (6). For splicing reaction, the spliceosome recognizes exon-intron boundaries of the 5′-donor and 3′-acceptor splice site. Furthermore, specific sequence motifs within exons can positively or negatively influence the recognition of nearby splice sites (7). The activity of so-called exonic splicing enhancers or exonic splicing silencers can be modulated by splicing factors like SR proteins or hnRNPs, which in turn all...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Alternative splicing of human papillomavirus type-16 E6/E6* early mRNA is coupled to EGF signaling via Erk1/2 activation

Rosenberger

Arce

Langbein

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…13,14 Although virus positivity predicts a favorable outcome for TSCC, viral status in integrated or episomal forms and viral DNA load do not invariably correlate with the levels of viral oncogene transcripts, cell cycle protein expression, and prognosis. 15,16 CCRT will further complicate regulation of cell cycle, repair of DNA, and induction of apoptosis. Thus, it is worth identifying the extent to which the EBV existence and/ or HPV presence or integration by themselves or each by itself, and/or the p53, pRb, and/or p21 expression altered by virus and/or by chemical mutagens contribute to prognosis.…”

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confidence: 99%

Use of combined molecular biomarkers for prediction of clinical outcomes in locally advanced tonsillar cancers treated with chemoradiotherapy alone

Chung¹,

Lee²,

Horng

et al. 2008

Head & Neck

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Background. Environmental exposures to tobacco, alcohol, human papillomavirus (HPV) and/or Epstein-Barr virus (EBV), all of which can perturb multiple cell cycle proteins or tumor suppressors, have been implicated in the pathogenesis of different subsets of head and neck cancers. The aim of this study was to investigate to which extent the virus infection by itself, and/or the altered cell cycle proteins, contributes to prognosis in locally advanced tonsillar squamous cell carcinomas (TSCCs) treated with concurrent chemoradiotherapy (CCRT) alone.Methods. Serial tumor tissue arrays from archival samples were tested for the presence of HPV genome integration or EBV episome by means of DNA sequencing, realtime polymerase chain reaction (PCR), and in situ hybridization. Alterations of cell cycle proteins (p53, pRb, and p21) were evaluated by immunohistochemical staining. The association of viral presence with altered cell cycle proteins was correlated to clinical outcomes.Results. Of the 46 patients with the same T2N2bM0 stage IVA among consecutive patients with TSCC, 23 (50%) had integrated HPV DNA and only 1 (2%) had EBV episome. The HPV types detected were almost all HPV-16. A reduced expression pattern of p53, pRb, and p21 was noted in HPVpositive tumors, and the incremental number of alterations in the 3 proteins was significantly associated with HPV-negative tumors. The presence or absence of HPV together with the number of altered expression of the 3 cell cycle markers resulted in further identification of 4 biologically and clinically distinct subgroups with different outcomes after CCRT.Conclusions. Use of combined biomarkers of oncogenic HPV and tumor suppressors of p53, pRb, and p21 in advanced TSCC provides prognostic molecular classification superior to the TNM stage system and identifies low-risk patients for organ preservation by CCRT alone and high-risk patients who might benefit from planned tonsillectomy and neck dissection before

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“…It is believed that the integration arises in high grade lesions, such as CIN2 and CIN3 and the deregulation of E6 and E7 expression may increase or remain at a constitute level. [92,93] In this scheme, flat warts can be resembled in CIN1 lesions, however the proliferation level of the cell is lower in the basal and parabasal layers. [13] Increased expression levels of E6 and E7 in high-risk HPV type infections causes CIN2+ phenotypes.…”

Section: Lower Genital Tract Neoplasias: Cervical Vaginal and Vulvarmentioning

confidence: 99%

The role of human papillomaviruses in cancer progression

Tulay¹,

Serakıncı²

2016

JCMT

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The importance of human papillomavirus (HPV) infection and its role in the progress of cancer have been widely evaluated. The understanding of HPV association with certain cancers, such as cervical cancer, is very well established. A big step forward in the prevention of HPV associated cancers with the use of early detection by screening strategies has also been taken. In the last decade, development of HPV vaccination has reduced the number of cases in HPV infections and infection induced cancers. In this report, we review the HPV pathogenesis and highlight the mechanism of HPV involvement in cancer development.

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Integration of the HPV16 genome does not invariably result in high levels of viral oncogene transcripts

Cited by 112 publications

References 39 publications

Alternative splicing of human papillomavirus type-16 E6/E6* early mRNA is coupled to EGF signaling via Erk1/2 activation

Alternative splicing of human papillomavirus type-16 E6/E6* early mRNA is coupled to EGF signaling via Erk1/2 activation

Use of combined molecular biomarkers for prediction of clinical outcomes in locally advanced tonsillar cancers treated with chemoradiotherapy alone

The role of human papillomaviruses in cancer progression

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