Immortalization of oral keratinocytes by functional inactivation of the p53 and pRb pathways

  title={Immortalization of oral keratinocytes by functional inactivation of the p53 and pRb pathways},
  author={Serge J. Smeets and Marlon van der Plas and Tieneke B.M. Schaaij-Visser and Eva A.M. van Veen and Johan van Meerloo and Boudewijn J. M. Braakhuis and Renske D. M. Steenbergen and Ruud H. Brakenhoff},
  journal={International Journal of Cancer},
A subgroup of head and neck squamous cell carcinomas (HNSCCs) contains high‐risk human papillomavirus‐type 16 (HPV16). The viral E6 and E7 oncoproteins inactivate the p53 and pRb proteins, respectively. We examined the causative effect of HPV16 E6 and E7 expression on the immortalization of normal oral keratinocytes (OKCs) and compared the resulting phenotype with alternative ways of p53‐ and pRb‐pathway abrogation frequently found in HNSCCs without HPV. Primary OKCs were conditionally… 

Human Papillomavirus (HPV)-Positive Head and Neck Cancer and the Wnt Signaling Pathway

This chapter summarizes the possible cell pathways involved in the activation of Wnt signaling in HPV-positive head and neck cancer.

Molecular genetic characterization of p53 mutated oropharyngeal squamous cell carcinoma cells transformed with human papillomavirus E6 and E7 oncogenes

The data suggest that upregulated STAT1 and interferon signals by HPV16 E6 and E7 genes may play a major role in the relatively favorable prognosis for HPV-positive oropharyngeal squamous cell carcinoma cases with non-disruptive p53 mutations.

Advances in Tumor Virology Role of HPV in Head and Neck Cancer

The experimental and epidemiological data provide robust evidence for a causal role in OPSCC, but the evidence for association of HPV with other HNSCC such as oral cavity or larynx is weak.

miR-31 is upregulated in oral premalignant epithelium and contributes to the immortalization of normal oral keratinocytes.

It can be concluded that miR-31 collaborates with hTERT to immortalize NOKs and that this may contribute to early stage oral carcinogenesis.

A Non-oncogenic HPV 16 E6/E7 Vaccine Enhances Treatment of HPV Expressing Tumors

The generation of an HPV16 E6/E7 construct is described, which contains mutations that render E6-E7 non-oncogenic, while preserving antigenicity, and which statistically enhances clearance of established HPV(+) cancer in vivo.

The role of human papillomavirus in p16‐positive oral cancers

  • Simone BelobrovA. Cornall M. McCullough
  • Biology, Medicine
    Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology
  • 2018
It is shown that the presence of transcriptionally active HPV rarely occurs inOSCC and that p16 is not an appropriate surrogate marker for HPV in OSCC cases, and it is proposed that non-viral mechanisms are responsible for the majority of IHC p16 overexpression in OS CC.

Identification of High-Risk Human Papillomavirus DNA, p16, and E6/E7 Oncoproteins in Laryngeal and Hypopharyngeal Squamous Cell Carcinomas

A high prevalence of HPV16 as a primary HR-HPV type in LSCC and HPSCC is suggested and the lack of HPV E6/E7 oncoproteins in some tumor samples may suggest either the absence of viral integration or the presence of other mechanisms of tumorigenesis.



E6 and e7 gene silencing and transformed phenotype of human papillomavirus 16-positive oropharyngeal cancer cells.

Repression of E6 and E7 oncogenes results in restoration of p53 and pRb suppressor pathways and induced apoptosis in HPV16-positive oropharyngeal squamous cell cancer cell lines.

A Two-Stage, p16INK4A- and p53-Dependent Keratinocyte Senescence Mechanism That Limits Replicative Potential Independent of Telomere Status

It is confirmed that keratinocytes undergo p16-related senescence during growth in culture, whether in the fibroblast feeder cell system or in the specialized K-sfm medium formulation, and that this mechanism can act as a barrier to immortalization following hTERT expression.

Papillomavirus E6 and E7 proteins and their cellular targets.

Current insights into E6 and E7 interactions with specific cellular targets that stimulate aspects of the viral life cycle, interfere with cell cycle controls and promote carcinogenic processes are summarized.

Involvement of intact HPV16 E6/E7 gene expression in head and neck cancers with unaltered p53 status and perturbed pRb cell cycle control

The data demonstrate that HPV16 DNA-positivity in head and neck cancers is not indicative of a causal role, and the E6 gene is found to be disrupted in most p53-mutated tumours without E6/E7 expression.

HPV-mediated transformation of the anogenital tract.

Genome-wide DNA copy number alterations in head and neck squamous cell carcinomas with or without oncogene-expressing human papillomavirus

Detailed genome analysis of head and neck squamous cell carcinomas with and without HPV16 involvement shows that HNSCC arising by environmental carcinogens are characterized by genetic alterations that differ from those observed in HPV16-induced H NSCC, and most likely occur early in carcinogenesis.

Creating oral squamous cancer cells: A cellular model of oral–esophageal carcinogenesis

  • G. GoesselM. Quante O. Opitz
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 2005
A transformation model creating oral–esophageal cancer cells is demonstrated by using a limited set of genetic alterations frequently observed in the corresponding human cancer to induce immortalization and malignant transformation of normal human epithelial cells.

Immortalisation of human ovarian surface epithelium with telomerase and temperature-sensitive SV40 large T antigen.

Evidence for a causal association between human papillomavirus and a subset of head and neck cancers.

It is suggested that HPV-positive oropharyngeal cancers comprise a distinct molecular, clinical, and pathologic disease entity that is likely causally associated with HPV infection and that has a markedly improved prognosis.

Comparison of p16INK4a expression with p53 alterations in head and neck cancer by tissue microarray analysis

It is suggested that loss of p16INK4a expression and p53 alterations should be viewed as related events involved in the early carcinogenic process.