The Role of Human Papillomaviruses in Oncogenesis

Mighty, Kristen K.; Laimins, Laimonis A.

doi:10.1007/978-3-642-38965-8_8

Cited by 63 publications

(60 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous work has shown that the loss of either E6 or E7 function in HeLa cells, and in other HPV-transformed cells, results in senescence, cell cycle arrest, and, in the case of E6 repression, also apoptosis (2,3,5). To test whether RGNs specific for E6 or E7 would exert the predicted phenotypic effect, we analyzed growth in culture of cells expressing S. pyogenes Cas9 and either E6 sgRNA1 or E7 sgRNA1 compared to that of cells expressing a control sgRNA.…”

Section: Resultsmentioning

confidence: 99%

“…4, but also senescence and/or apoptosis (2,3,5,6,8). Therefore, it is expected that the expression of Cas9/ sgRNA combinations specific for E6 or E7 would initially inhibit cell growth, followed by induction of cell death.…”

Section: Resultsmentioning

confidence: 99%

“…ervical carcinomas arise as a result of infection by human papillomavirus (HPV), most commonly high-risk HPV serotype HPV-16 or HPV-18 (1)(2)(3)(4). Tumorigenesis results primarily from the deregulated expression of two viral oncoproteins, termed E6 and E7, which induce the degradation of the host cell tumor suppressors p53 and retinoblastoma (Rb) protein, respectively (2)(3)(4)(5)(6)(7).…”

mentioning

confidence: 99%

“…Tumorigenesis results primarily from the deregulated expression of two viral oncoproteins, termed E6 and E7, which induce the degradation of the host cell tumor suppressors p53 and retinoblastoma (Rb) protein, respectively (2)(3)(4)(5)(6)(7). This suggests that inactivation of either E6 or E7 expression in cervical carcinoma cells should result in the induction of p53 or Rb, respectively, as these proteins normally remain fully intact in cervical carcinoma cells.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Inactivation of the Human Papillomavirus E6 or E7 Gene in Cervical Carcinoma Cells by Using a Bacterial CRISPR/Cas RNA-Guided Endonuclease

Kennedy

Kornepati

Goldstein

et al. 2014

J Virol

251

205

View full text Add to dashboard Cite

High-risk human papillomaviruses (HPVs), including HPV-16 and HPV-18, are the causative agents of cervical carcinomas and are linked to several other tumors of the anogenital and oropharyngeal regions. The majority of HPV-induced tumors contain integrated copies of the normally episomal HPV genome that invariably retain intact forms of the two HPV oncogenes E6 and E7. E6 induces degradation of the cellular tumor suppressor p53, while E7 destabilizes the retinoblastoma (Rb) protein. Previous work has shown that loss of E6 function in cervical cancer cells induces p53 expression as well as downstream effectors that induce apoptosis and cell cycle arrest. Similarly, loss of E7 allows increased Rb expression, leading to cell cycle arrest and senescence. Here, we demonstrate that expression of a bacterial Cas9 RNA-guided endonuclease, together with single guide RNAs (sgRNAs) specific for E6 or E7, is able to induce cleavage of the HPV genome, resulting in the introduction of inactivating deletion and insertion mutations into the E6 or E7 gene. This results in the induction of p53 or Rb, leading to cell cycle arrest and eventual cell death. Both HPV-16-and HPV-18-transformed cells were found to be responsive to targeted HPV genome-specific DNA cleavage. These data provide a proof of principle for the idea that vector-delivered Cas9/sgRNA combinations could represent effective treatment modalities for HPV-induced cancers. IMPORTANCEHuman papillomaviruses (HPVs) are the causative agents of almost all cervical carcinomas and many other tumors, including many head and neck cancers. In these cancer cells, the HPV DNA genome is integrated into the cellular genome, where it expresses high levels of two viral oncogenes, called E6 and E7, that are required for cancer cell growth and viability. Here, we demonstrate that the recently described bacterial CRISPR/Cas RNA-guided endonuclease can be reprogrammed to target and destroy the E6 or E7 gene in cervical carcinoma cells transformed by HPV, resulting in cell cycle arrest, leading to cancer cell death. We propose that viral vectors designed to deliver E6-and/or E7-specific CRISPR/Cas to tumor cells could represent a novel and highly effective tool to treat and eliminate HPV-induced cancers. C ervical carcinomas arise as a result of infection by human papillomavirus (HPV), most commonly high-risk HPV serotype HPV-16 or HPV-18 (1-4). Tumorigenesis results primarily from the deregulated expression of two viral oncoproteins, termed E6 and E7, which induce the degradation of the host cell tumor suppressors p53 and retinoblastoma (Rb) protein, respectively (2-7). This suggests that inactivation of either E6 or E7 expression in cervical carcinoma cells should result in the induction of p53 or Rb, respectively, as these proteins normally remain fully intact in cervical carcinoma cells. In fact, repression of E6 expression not only induces p53 but also upregulates the downstream effectors of p53 function, including proapoptotic proteins and the cyclin-dependent kinase inhibitor...

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Inactivation of the Human Papillomavirus E6 or E7 Gene in Cervical Carcinoma Cells by Using a Bacterial CRISPR/Cas RNA-Guided Endonuclease

Kennedy

Kornepati

Goldstein

et al. 2014

J Virol

251

205

View full text Add to dashboard Cite

show abstract

“…The reported prevalence of HPV-DNA (varying from 0% to 100%) in these lesions result still very discordant probably due the perseverant extreme heterogeneity of investigating study methodology in terms of: i) different patient profiles, ii) the site of lesion, iii) diverse specimen types, iv) not uniform dissimilar methods of sampling storage; v) variable sensitivity of viral detection procedures and vi) intrinsic pathophysiology of the oral mucosa and lesions [2][3][4]. In relation to this latest aspect, the histological and clinical variability of OPMD and its implication with structural characteristics of HPV infection, has been little investigated.…”

Section: Introductionmentioning

confidence: 99%

Human Papillomavirus (HPV) Detection in Keratotic Variants of Oral Lichen Planus: Negative Results in a Preliminary Open Study

2017

ARC Journal of Dental Science

View full text Add to dashboard Cite

Abstract:Background During the last few decades, several researches have been identified HPV genomic sequences in Head Neck Squamous Cell Carcinomas (HNSCC) and in Oral Potentially Malignant Disorders (OPMD) hypothesizing a possible viral etiological role. However, the reported prevalence of HPV-DNA (varying from 0% to 100%) in these lesions result still very discordant.Objective Human papillomavirus (HPV) infection in Oral Lichen Planus (OLP) has been largely investigated but not so extensively with respect to its morphological/histopathological features. The possible influence of hyper-keratosis/parakeratosis in HPV detection for keratotic variants of OLP is here proposed and investigated.Materials and methods A total of 45 individuals with keratotic variants of OLP, clinically and histologically confirmed, were consecutively enrolled, before starting any treatment, and underwent oral brushing for HPV investigation. Viral DNA was extracted from oral brushed cells and HPV DNA researched by the combined use of the INNO-LiPA HPV Genotyping system (Innogenetics) and a PCR assay coupled with genome sequencing.Results None of cytological samples collected resulted HPV-positive. ConclusionsIn this preliminary study, oral HPV infection, investigated by means of a non-invasive oral sampling procedure and a standardized approach for HPV DNA detection, was not showed in any of the investigated cases. The presence of epithelial hyper-keratosis/parakeratosis in some variants of OLP could be a possible cause of impenetrability and/or difficult detection of the virus. Indeed, in case of keratotic variants of OLP, the possible potential false-negative results of HPV investigation by cytological procedure might be possible; on consequence, an alternative approach for viral detection (i.e. by histological sampling) should be considered.

show abstract

Analysis of the integration of human papillomaviruses in head and neck tumours in relation to patients' prognosis

Vojtechova

Sabol

Saláková

et al. 2015

Intl Journal of Cancer

View full text Add to dashboard Cite

Integration, which leads to the disruption of the circular HPV genome, is considered as a critical, albeit not obligatory, step in carcinogenic progression. Although cervical carcinomas with extrachromosomal HPV plasmid genomes have been described, the virus is integrated in 70% of HPV16-positive cervical tumours. Limited information is available about HPV integration in head and neck tumours (HNC). In this study, we have characterised the physical status of HPV in a set of tonsillar tumour samples using different methods-the mapping of E2 integration breakpoint at the mRNA level, the 3' RACE based Amplification of Papillomavirus Oncogene Transcripts (APOT) assay and Southern blot. Furthermore, the impact of HPV integration on patients' prognosis has been evaluated in a larger set of 186 patients with head and neck cancer. Based on the analysis of E2 mRNA, HPV was integrated in the host genome in 43% of the HPV-positive samples. Extrachromosomal or mixed form was present in 57%. In fresh frozen samples, the APOT and E2 mapping results were in agreement. The results were confirmed using Southern blotting. Furthermore, the type and exact site of integration were determined. The survival analysis of 186 patients revealed HPV positivity, tumour size and lymph node positivity as factors that influence disease specific survival. However, no statistically significant difference was found in disease specific survival between patients with HPV-positive integrated vs. extrachromosomal/mixed forms of the virus.Head and neck cancer (HNC) is the seventh most common cancer in men and the 13 th most common cancer in women worldwide and its incidence is on the rise in some anatomical sites 1 . HNC has at least two different etiologies. Most HNC cases are associated with smoking and alcohol consumption, which induce mutations in important pathways 2,3 . However, 26% of all HNC and up to 50% of oropharyngeal tumours are associated with the presence and expression of mucosal high-risk human papillomaviruses (Alfa HR-HPV; HR-HPVs) [4][5][6] . Mucosal HRHPVs also cause cervical cancer and other neoplasms of anogenital skin and mucosae. The most common mucosal HR-HPV is HPV16, which is found in almost 90% of HPV-positive HNC, other common types being HPV18, HPV33 and HPV52 6,7 . Patients with HPV-associated HNC have a better prognosis, overall survival, and response to treatment 4 . The mechanisms of Alfa HR-HPV-induced carcinogenesis, regardless of the anatomical site, rely on the functions of viral oncoproteins, E6 and E7, as they inactivate tumour

show abstract

The Role of Human Papillomaviruses in Oncogenesis

Cited by 63 publications

References 58 publications

Inactivation of the Human Papillomavirus E6 or E7 Gene in Cervical Carcinoma Cells by Using a Bacterial CRISPR/Cas RNA-Guided Endonuclease

Inactivation of the Human Papillomavirus E6 or E7 Gene in Cervical Carcinoma Cells by Using a Bacterial CRISPR/Cas RNA-Guided Endonuclease

Human Papillomavirus (HPV) Detection in Keratotic Variants of Oral Lichen Planus: Negative Results in a Preliminary Open Study

Analysis of the integration of human papillomaviruses in head and neck tumours in relation to patients' prognosis

Contact Info

Product

Resources

About