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Oral microbiome and carcinogenesis
Šimáčková, Šárka ; Šmahelová, Jana (advisor) ; Horníková, Lenka (referee)
Microorganisms that colonize human body participate to well functioning of human organism and they are very important for human health. The composition of these communities (microbiomes) is specific for everyone and changes in the composition may participate to induce and progression of disease. These diseases also include carcinogenesis and tumors. Main goal of this work are specially tumors in head and neck area which risk factors are smoking, alcohol consumption and human papillomaviruses infection. Depending on these factors is influenced the composition of microbiome of oral cavity. Many studies show differences between oral microbiomes of patients with head and neck cancer and healthy people as controls. Keywords: microbiome, oral cavity, head and neck cancer, papillomavirus
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The role of APOBEC proteins in HPV-induced carcinogenesis
Frolíková, Daniela ; Šmahelová, Jana (advisor) ; Šroller, Vojtěch (referee)
Apolipoprotein B mRNA editing enzyme, catalytic polypeptide (APOBEC) are a family of evolutionarily conserved cytidine deaminases with the ability to bind and modify RNA and/or ssDNA. APOBEC1-4 have a number of functions in cells. Members of the APOBEC3 subfamily cause restriction of foreign nucleic acids, retrotransposons and viruses, including human papillomaviruses (HPV), and may contribute to the clearance of infection. Certain HPVs are referred to as oncogenic viruses because of their ability to induce immortalization and transformation of epithelial cells via E5, E6 and E7 oncoproteins. E6 and E7 can also induce transcription or inhibit degradation of some APOBEC3. This results in an increase in their levels in cells. APOBEC3 also act as cellular mutators, as they can catalyze deaminations on transiently produced ssDNA during replication or transcription. Deregulation of APOBEC3 caused by oncoproteins may contribute to mutagenesis. This bachelor thesis focuses on APOBEC proteins, their activation and function during HPV-induced carcinogenesis, and in particular the extent and consequences of APOBEC3 mutations. Keywords: APOBEC, mutagenesis, papillomavirus, oncoproteins, carcinogenesis
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The detection of hypoxic markers in head and neck tumours
Šťovíčková, Eliška ; Šmahelová, Jana (advisor) ; Rösel, Daniel (referee)
Head and neck cancers (HNSCC) are heterogeneous group of tumours. Risk factors are mainly smoking and alcohol consumption. Some of these tumours are associated with human papillomavirus (HPV) infection, which is a significant positive prognostic factor. These tumours differ from HPV-negative tumours in clinicopathological characteristics, tumour microenvironment and response to treatment. Hypoxia is commonly found in tumors including HNSCC and is a significant prognostic and predictive factor. Elucidating the degree of hypoxia in relation to HPV infection could partly explain the differences in prognosis of these patients and allow more appropriate choice of therapy. Aspartate-β-hydroxylase is also a significant negative prognostic factor in a number of tumours, but its role in HNSCC has not yet been investigated. I focused on the detection of hypoxic markers and aspartate-β-hydroxylase expression in samples from HNSCC patients at the mRNA level by quantitative PCR and at the protein level by multispectral immunohistochemistry. The expression levels of these markers were compared in tumors stratified according to viral etiology and other characteristics such as smoking, localization or tumor stage. HPV infection had the highest impact on the expression of these markers, but the results cannot point to a...
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Histone modifications and methylation of polyomaviral genomes during the infection
Mrkáček, Michal ; Forstová, Jitka (advisor) ; Šmahelová, Jana (referee)
Similarly to other viruses, polyomaviruses require for their successful replication enzymes and other proteins encoded by their host cells. Additionally, because of their relatively small genome with only a few genes, polyomaviruses utilize for their efficient replication cellular regulation mechanisms. One of these regulations are posttranslational modifications of histones, which form nucleosomes together with viral DNA. The spectrum of these modifications is very wide, but in case of polyomaviruses, almost only ones studied are histone acetylations and methylations. Second possible regulation is a methylation of cytosine in CpG dinucleotides, which is associated with repression of gene expression. Current knowledge however suggest that polyomaviruses do not utilise this kind of modification. Moreover, because of a relatively small amount of CpG dinucleotides present in their genomes, they seem to avoid it. The goal of this work is to describe the individual types of these modifications and show their possible importance in the infectious cycle of polyomaviruses. Key words: polyomavirus, epigenetics, histone modification, DNA methylation, CpG dinucleotides
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DNA/RNA intercalating agents as antivirotics: possible mechanisms of action
Kropáček, Václav ; Španielová, Hana (advisor) ; Šmahelová, Jana (referee)
DNA/RNA intercalating agents are compounds with capability to insert themself between nucleic acids base pairs. This phenomenon is accompanied by structural or functional disruption of said nucleic acid. Some of these compounds are used as therapeutics for cancer, bacterial or parasital infection or are used as antivirotics. This work summarizes different mechanisms which are responsible for antiviral effects of three significant classes of intercalating agents, acridine derivates, quinolines and quinolones. Except for intercalation into nucleic acids, these compounds are also capable of alkalization of cellular organels, inhibition of some viral enzymes (helicase, integrase) and immunomodulation. These abilities enables them to disrupt viral life cycle.
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Influencing Notch signalling in virus associated tumours
Bujnovská, Ludmila ; Šmahelová, Jana (advisor) ; Grantz Šašková, Klára (referee)
The Notch signalling pathway affects cell differentiation, apoptosis and proliferation. It is an evolutionarily conserved signalling pathway important during embryogenesis and ontogenesis. Its deregulation can lead to carcinogenesis. Cells of various tumour types often contain gene mutations or other abnormalities in the Notch pathway. Its function with regard to oncogenesis has a dual character - in some cases it acts as an oncogenic pathway, in others it has a tumour-suppressive effect. This depends on the cellular context. A large group of tumours with proven abnormalities in the Notch signalling are head and neck squamous cell carcinomas (HNSCC). It is the 7th most common tumour type and the lethality rate is high. Almost 25 % of these tumours are etiologically related to human papillomavirus (HPV) infection. The cell cycle signalling pathways, including the Notch pathway, are the primary target of oncogenic viruses where HPV are no exception. This thesis describes changes in the Notch signalling pathway in HPV-induced HNSCC and the effect of viral oncoproteins E6 and E7 on this signalling pathway.
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Mechanisms of papillomavirus genome integration into the human chromosome
Frčková, Tereza ; Šmahelová, Jana (advisor) ; Fraiberk, Martin (referee)
Human papillomaviruses (HPV) are small non-enveloped DNA viruses that can cause malignancies in the human population. They are often associated with carcinomas in anogenital area in both men and women, but also with part of head and neck cancer. In infected cells, the HPV genome is present as a circular molecule of DNA, called an episom. Certain circumstances result into the occurrence of a linearization of the HPV genome and a subsequent integration in the human chromosome. The integration plays a role in the cell behavior and contributes to immortalization and tumor transformation. The HPV genome integration is influenced by various viral or cell factors that affect the HPV genome stability in the cell. Interaction between viral and cell protein can often lead to activation of DNA damage response, that virus exploits for replication of viral genome. Viral genome integration is also more likely to occur in certain HPV types. Another factor is the area of infection, where the neoplastic progression was studied.
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Biological treatment and its influence on the course of latent viral infections in patients with psoriasis
Laurin, Josef ; Šmahelová, Jana (advisor) ; Janovec, Václav (referee)
There are more than 80 identified autoimmune diseases. One of the most prevalent ones is psoriasis. Its prevalence is around 2-5 % worldwide. The treatment of this inflammatory skin disease can be divided as follows: in cases of low severity, topical therapies are used for local treatment and in the cases of insufficient effect, stronger therapies are used. Phototherapy is used for moderate severity, and systemic therapy is used in moderate to severe disease. Systemic agents include cytostatic methotrexate, immunosuppressant cyclosporin, or retinoids (vitamin A analogues). However, even systemic therapies may not yield the desired effects or may have adverse effects on the overall condition of the patient. In those cases, biological therapy comes to use. Biological therapy is usually conducted using antibodies and fusion proteins, which are made using recombinant technologies. Tumour necrosis factor α (TNF-α) and interleukin 12, 17 and 23 (IL-12, IL-17 and IL-23) inhibitors are the most commonly used in the treatment of psoriasis. During the inhibition of the immune system, it has been confirmed that a reactivation of viral infections can occur. These reactivations may subsequently lead to the development of various diseases caused by latent viral infections.
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Characterization of viral nanoparticles derived from mouse papillomavirus
Vomáčka, Petr ; Španielová, Hana (advisor) ; Šmahelová, Jana (referee)
The L1 and L2 capsid proteins of papillomaviruses are characterized by the ability to self- assemble into viral capsids, which can be divided into pseudovirions (PsVs) and virus-like particles (VLPs) by inner content. In addition to the fact that such particles can serve as "nano-containers" for diagnostic and therapeutic agents, it has also been shown that papillomaviruses, whether wild, PsVs or VLPs have a higher affinity for tumor tissue than non-tumor tissue. This thesis deals with relatively newly discovered (2011) mouse papillomavirus (MusPV) and nanoparticles derived from this virus. This papillomavirus has been chosen for its positives, including easy preparation of VLPs and PsVs, as well as an available model organism for possible testing. Furthermore, MusPV has the potential for use in gene therapy and cancer diagnosis, because there is no immune response in the human population. The aim of this diploma thesis is to prepare an expression system for the production of PsVs and VLPs. In additional it will also look at the quality and quantity of PsVs and VLPs, characterization of these particles and verification of existing postulates regarding higher affinity of papillomaviruses for tumor cells. Finally, it will also to verify whether the same effect is observed in MusPV. In the results of...
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