BACKGROUND: Human papillomaviruses (HPVs) induce a subset of head and neck squamous cell carcinomas (HNSCC) and anogenital cancers, particularly cervical cancer (CC). The major viral proteins that contribute to tumorigenesis are the E6 and E7 oncoproteins, whose expression is usually enhanced after the integration of viral DNA into the host genome. Recently, an alternative tumorigenesis pathway has been suggested in approximately half of HNSCC and CC cases associated with HPV infection. This pathway is characterized by extrachromosomal HPV persistence and increased expression of the viral E2, E4, and E5 genes. The E6, E7, E5, and E2 proteins have been shown to modify the expression of numerous cellular immune-related genes. The antitumor immune response is a critical factor in the prognosis of HPV-driven cancers, and its characterization may contribute to the prediction and personalization of the increasingly used cancer immunotherapy. METHODS: We analyzed the immune characteristics of HPV-dependent tumors and their association with carcinogenesis types. Transcriptomic HNSCC and CC datasets from The Cancer Genome Atlas were used for this analysis. RESULTS: Clustering with immune-related genes resulted in two clusters of HPV16-positive squamous cell carcinomas in both tumor types: cluster 1 had higher activation of immune responses, including stimulation of the antigen processing and presentation pathway, which was associated with higher immune cell infiltration and better overall survival, and cluster 2 was characterized by keratinization. In CC, the distribution of tumor samples into clusters 1 and 2 did not depend on the level of E2/E5 expression, but in HNSCC, most E2/E5-high tumors were localized in cluster 1 and E2/E5-low tumors in cluster 2. Further analysis did not reveal any association between the E2/E5 levels and the expression of immune-related genes. CONCLUSIONS: Our results suggest that while the detection of immune responses associated with preserved expression of genes encoding components of antigen processing and presentation machinery in HPV-driven tumors may be markers of better prognosis and an important factor in therapy selection, the type of carcinogenesis does not seem to play a decisive role in the induction of antitumor immunity.

• MeSH
• dlaždicobuněčné karcinomy hlavy a krku komplikace   MeSH
• infekce papilomavirem * komplikace   MeSH
• karcinogeneze genetika   MeSH
• lidé MeSH
• lidské papilomaviry MeSH
• nádory děložního čípku * MeSH
• nádory hlavy a krku * genetika   komplikace   MeSH
• onkogenní proteiny virové * genetika   metabolismus   MeSH
• Papillomavirus E7 - proteiny genetika   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Papilomavírusy patria medzi vírusy s dvojvláknovou DNA (dsDNA). Sú schopné navodiť tak tvorbu benígnych, ako aj malígnych nádorov. Spojitosť medzi infekciou ľudskými papilomavírusmi (HPV) a rakovinou krčka maternice bola detailne opísaná len nedávno vďaka profesorovi zur Hausenovi. Avšak existujú zástupcovia HPV vírusov, u ktorých nebola dokázaná asociácia s vytváraním malignít. Preto rozoznávame tzv. vysoko-(HR) a nízkorizikové (LR) typy papilómov. V našej práci opisujeme životný cyklus HPV, molekulárne mechanizmy počas onkogenézy a snažíme sa o porovnanie HR HPV a LR HPV.

Papillomaviruses belong to a group of viruses with double-stranded DNA (dsDNA). These viruses are believed to induce benign as well as malignant tumour growth. Thanks to professor zur Hausen, the connection between the infection by human papillomaviruses (HPV) and cervix cancer was described in detail a few years ago. However, there exist certain types of HPV viruses, in which no association with malignancies was ever demonstrated. Hence, we can divide HPV into „high-risk“ (HR) and „low-risk“ (LR) group. Our work describes the life cycle of HPV, molecular mechanisms of oncogenesis and aims to compare HR HPV and LR HPV within these terms. Key words: viral cell transformation – oncogene protein E6 – oncogene protein E7 – E5 protein HPV-16 – „high-risk“ – „low-risk“ The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers. Submitted: 28. 6. 2013 Accepted: 14. 7. 2013

• MeSH
• Alphapapillomavirus MeSH
• DNA virů genetika   MeSH
• infekce DNA virem * MeSH
• infekce papilomavirem * genetika   MeSH
• interferony MeSH
• lidé MeSH
• nádorová transformace buněk MeSH
• nádorový supresorový protein p53 MeSH
• onkogenní proteiny virové * genetika   metabolismus   MeSH
• Papillomavirus E7 - proteiny MeSH
• retinoblastomový protein MeSH
• Check Tag
• lidé MeSH

Human papillomaviruses (HPV) are small circular, double-stranded DNA viruses infecting epithelial tissues. HPV types can be classified both as high-risk or low-risk. Of the more than 120 different identified types of HPV, the majority are involved in infections of the genital tract, cancer of the cervix, vulva, vagina and penis, and of non-anogenital localizations, such as the head and neck areas. From the point of view of the infection, human papillomaviruses have developed several molecular mechanisms to enable infected cells to suppress apoptosis. This review provides a comprehensive and critical summary of the current literature that focuses on cervical carcinoma and cancer of the head and neck caused by HPV. In particular, we discuss HPV virology, the molecular mechanisms of carcinogenesis, the role of the tumor suppressor protein p53 and the E6/E7 zinc finger proteins. Classification of HPV according to diagnosis is also described.

• MeSH
• infekce papilomavirem metabolismus   patologie   MeSH
• lidé MeSH
• metalothionein metabolismus   MeSH
• nádorová transformace buněk MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• nádory děložního čípku virologie   MeSH
• nádory hlavy a krku klasifikace   virologie   MeSH
• onkogenní proteiny virové metabolismus   MeSH
• Papillomaviridae metabolismus   MeSH
• Papillomavirus E7 - proteiny metabolismus   MeSH
• represorové proteiny metabolismus   MeSH
• tyrosinkinasy metabolismus   MeSH
• zinkové prsty MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Transient expression of foreign genes based on plant viral vectors is a suitable system for the production of relevant immunogens that can be used for the development of a new generation of vaccines against a variety of infectious diseases. In the present study the epitope derived from HPV-16 L2 minor capsid protein (amino acids 108-120) was expressed from Potato virus X (PVX)-based vector pGR106 as N- or C-terminal fusion with the PVX coat protein (PVX CP) in transgenic Nicotiana benthamiana plants. The fusion protein L2 108-120-PVX CP was successfully expressed in plants at a level of 170 mg/kg of fresh leaf tissue. The C-terminal fusion protein PVX CP- L2 108-120 was expressed using mutated vector sequence to avoid homologous recombination at a level of 8 mg/kg of fresh leaf tissue. Immunogenicity of L2 108-120-PVX CP virus-like particles was tested after immunization of mice by subcutaneous injection or tattoo administration. In animal sera the antibodies against the PVX CP and the L2 108-120 epitope were found after both methods of vaccine delivery.

• MeSH
• elektroforéza v polyakrylamidovém gelu MeSH
• ELISA MeSH
• epitopy genetika   metabolismus   MeSH
• genetické vektory genetika   MeSH
• geneticky modifikované rostliny MeSH
• imunizace MeSH
• klonování DNA MeSH
• lidé MeSH
• listy rostlin metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• oligonukleotidy genetika   MeSH
• onkogenní proteiny virové metabolismus   MeSH
• protilátky virové krev   MeSH
• rekombinantní fúzní proteiny imunologie   metabolismus   MeSH
• tabák metabolismus   MeSH
• transmisní elektronová mikroskopie MeSH
• virion imunologie   MeSH
• virové plášťové proteiny metabolismus   MeSH
• western blotting MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• antitumorózní látky alkylující terapeutické užití   MeSH
• cyklofosfamid terapeutické užití   MeSH
• imunoterapie MeSH
• lidé MeSH
• nádorová transformace buněk MeSH
• nádory terapie   MeSH
• onkogenní proteiny virové metabolismus   MeSH
• represorové proteiny metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• srovnávací studie MeSH

• MeSH
• DNA vazebné proteiny MeSH
• genetická transkripce MeSH
• homeodoménové proteiny metabolismus   MeSH
• jaderné proteiny metabolismus   MeSH
• kultivované buňky MeSH
• kuřecí embryo MeSH
• lidé MeSH
• onkogenní proteiny virové metabolismus   MeSH
• zvířata MeSH
• Check Tag
• kuřecí embryo MeSH
• lidé MeSH
• zvířata MeSH

Cell cycle proteins regulate the transitions from G1 to S and G2 to M phases. In higher eukaryotes, their function is controlled by intracellular cascades regulated by extracellular growth factors. We have studied in previously described transgenic mouse models for thyroid proliferative diseases the expression of the key proteins regulating the cell cycle by Western blotting and immunohistochemistry, and have correlated the observations with the known actions of the transgenes on the signal transduction cascades. In the adenosine A2a receptor model, the cyclic AMP pathway, upstream of the Rb family cell division block, is constitutively activated. In the model expressing HPV 16 E7 protein, the Rb-like proteins are inhibited. Cyclin-dependent kinases cdk4, cdk2 and cdc2, and the associated cyclins D, E and A have been studied. Cyclin D3 appears as the major cyclin D subtype expressed in mouse thyroid epithelial cells in normal and transgenic mice. In the adenosine A2aR model, all cell cycle proteins tested were accumulated. In the E7 model, all cell cycle proteins except for D-type cyclins and cdk4 were also accumulated. A similar pattern was observed in thyroids coexpressing both transgenes, suggesting a dominant effect of E7 over the consequences of the cAMP cascade activation. The cyclin-dependent kinase inhibitors p21cip1/waf1 and p27kip1 were not downregulated in these proliferating thyroids which suggest other roles than the inhibition of the cell cycle progression.

• MeSH
• buněčná diferenciace MeSH
• buněčný cyklus MeSH
• cyklin A metabolismus   MeSH
• cyklin D MeSH
• cyklin E metabolismus   MeSH
• cyklin-dependentní kinasa 2 MeSH
• cyklin-dependentní kinasa 4 MeSH
• cyklin-dependentní kinasy metabolismus   MeSH
• cykliny metabolismus   MeSH
• inhibitor p21 cyklin-dependentní kinasy MeSH
• inhibitor p27 cyklin-dependentní kinasy MeSH
• inhibitory enzymů metabolismus   MeSH
• kinasy CDC2-CDC28 * MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši transgenní MeSH
• myši MeSH
• nádorové supresorové proteiny * MeSH
• nádory štítné žlázy metabolismus   MeSH
• onkogenní proteiny virové genetika   metabolismus   MeSH
• Papillomavirus E7 - proteiny MeSH
• protein-serin-threoninkinasy metabolismus   MeSH
• proteinkinasa CDC2 metabolismus   MeSH
• proteiny asociované s mikrotubuly metabolismus   MeSH
• proteiny buněčného cyklu metabolismus   MeSH
• proteiny metabolismus   MeSH
• protoonkogenní proteiny * MeSH
• purinergní receptory P1 genetika   metabolismus   MeSH
• receptor adenosinový A2A MeSH
• štítná žláza metabolismus   MeSH
• thyreoglobulin metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH