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STAT3 signalling pathway modulation and its impacts on cell phenotype, senescence and secretome.
Novotný, Ondřej ; Reiniš, Milan (advisor) ; Šmahel, Michal (referee)
Cellular senescence represents an effective barrier to tumour growth on the one hand, on the other hand, senescent cells secrete substances that create a protumourigenic environment. Understanding and influencing these processes will bring new approaches in the fight against tumours and other serious diseases. The IL-6/JAK2/STAT3 signalling pathway is crucial both in oncogenesis and in the induction of cellular senescence and it also has a major influence on the composition of the secretome of senescent cells. Targeted blockade of this pathway could therefore change the tumour microenvironment, either by directly affecting the induction of senescence itself, or by adjusting secretion and thereby by attenuation of the immunosuppressive environment induced by produced cytokines. The aim of this thesis is to find out whether and how inhibitors of the STAT3 signalling pathway can change the secretome of senescent and proliferating tumour cells. Based on the comparison of the toxicity and effectiveness of the STAT3 signalling pathway inhibition by Stattic analogues on proliferating TC-1 tumour cells, I selected two suitable inhibitor molecules for further experiments. I found out that these selected inhibitors significantly reduce the secretion of important pro-tumour signalling molecules by TC-1 tumour...
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Inhibition of P-glycoprotein-mediated multidrug resistance and STAT3 signaling pathway through polymeric conjugates bearing protease inhibitor derivatives
Starenko, Daniil ; Kovář, Marek (advisor) ; Truksa, Jaroslav (referee)
Tumor cells expressing high levels of some ABC transporters (mainly P-glycoprotein) can become resistant to many structurally and functionally different drugs. Such multidrug resistance can be a significant barrier for a successful chemotherapy of malignant diseases. There is a considerable amount of small-molecular-weight compounds capable of potent inhibition of P-glycoprotein, but none of them are approved for the clinical use. STAT3 is a transcription factor important for many physiological processes, but its constitutive activation may lead to the malignant transformation and chemotherapy resistance in tumor cells. This molecule is thus potential target for anticancer drugs. The inhibition of STAT3 signaling should lead to lower cancer cell proliferation and their increased susceptibility to induction of apoptosis. Considerable attention is given to increase the effectiveness and to lower the adverse effects of conventional cytostatic agents via using nanomaterials and drug delivery systems in the research of new cancer therapy approaches. Polymeric carriers based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers are promising candidates in this field. The main aim of this diploma thesis was to evaluate the effectiveness of several HIV protease inhibitor (ritonavir, lopinavir, indinavir,...
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Sequencing of the ZNF341 gene
POSPÍCHALOVÁ, Kateřina
In my bachelor thesis I dealt with the issue of the ZNF341 gene, which is associated with a defect in the STAT3 protein, causing the syndrome of hyperimmunoglobulinemia E. Hyper IgE syndrome is a multiorgan disease causing eczema, allergies, scoliosis and many other diseases. In the theoretical part, I focused on the ZNF341 gene, its characteristics, its location on the chromosome and the disease that causes its deficiency. Subsequently, I focused on the already mentioned disease of hyperimmunoglobulinemia E. In this disease, I investigated in what forms it occurs and what are its causes and consequences. I also mentioned in the theoretical part about the PCR method and DNA sequencing methods. In the practical part I processed 20 anonymized samples. For all samples I performed DNA isolation, PCR, electrophoresis, purification of PCR products. This was followed by preparation for Sanger sequencing. I sent the samples to GenSeq s.r.o. for sequencing because there was no appropriate sequencer in the school lab. In the final part of the bachelor thesis I evaluated the obtained sequences. I used the BioEdit program and the NCBI internet database to evaluate the sequences. I also received several sequences from children from the České Budějovice and Karviná regions. I then compared the incidence of gene mutations in these samples. Out of a total of 40 samples evaluated, I found a mutation in two of them. It was the same mutation that has not yet been described in the NCBI database.
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Role of STAT3 signalling in oncogenesis and cancer therapy
Machalová, Veronika ; Hodný, Zdeněk (advisor) ; Brábek, Jan (referee)
STAT3 (Signal Transducer and Activator of Transcription 3) is considered to be one of the possible targets of cancer treatment. The ability of STAT3 constitutive activation to form tumors is a foundation of such theories. Additionally, constitutively activated STAT3 is present in many types of cancer with high occurrence, such as breast and prostate carcinoma. This protein is required in normal body cells as well. STAT3 is a transcription factor targeting many genes that are essential for the cell. STAT3 is activated by phosphorylation of its tyrosine residue and homodimerization. Proteins transcribed with help of STAT3 function in cell cycle progression, cell growth, replication, negative regulation of apoptosis, and other roles, typical for cancer. Moreover, STAT3 is modulating mitochondrial function and maintaining ROS production in mitochondria, but in form of transcriptionally inactive monomers. The purpose of this Thesis is to review known data about STAT3 in oncogenesis and by that, to show STAT3 has great potential to become the target of cancer treatment. This Thesis contains a short overview of known STAT3 inhibitors as well. Key words: Signal Transducer and Activator of Transcription 3 (STAT3), JAK/STAT3 pathway, constitutive activation, cancer, tumor, inhibitor, mitochondria, apoptosis
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Pathologic STAT3 signalling pathway activation in cancer and viral diseases.
Podestátová, Barbora ; Reiniš, Milan (advisor) ; Škarková, Aneta (referee)
STAT3, one of the seven members of STAT protein family, is able to transduce signal into the nucleus, where it binds to specific DNA sequences and acts as a transcription factor. Under physiological conditions, STAT3 regulates genes associated with number of functions such as cell proliferation, differentiation, apoptosis or immune response. In the case of pathological conditions, STAT3 can be dysregulated or constitutively activated, which may result in cancerogenesis. During this process, STAT3 is frequently activated directly in tumor cells where it acts tumorigenically. STAT3 is also associated with inflammatory reactions mediated by immune cells, which along with tumor and stromal cells are involved in the formation of the tumor microenvironment. The role of STAT3 is also important in the fight against viral infections, and when STAT3 activated aberrantly, it can lead to chronic diseases, including cancer. Due to these serious roles during pathogenesis, STAT3 is the subject of research of various inhibitors that either directly inhibit the STAT3 molecule function or indirectly any of the components of its signaling pathway.
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Link between inflammation and cancer
Schierl, Jaroslav ; Poljaková, Jitka (advisor) ; Miarková, Eva (referee)
Chronic inflammation caused by many initiators can lead to a development of a tumor disease. Among these initiators, we found chronic infections as well as other biological, chemical or physical factors which have endogenous and exogenous origins as for example tobacco smoke, alcohol, radiation, obesity and others. The inflammatory response is orchestrated by immune system cells which contribute to a tumorigenesis by producing reactive oxygen and nitrogen species which harm cell structures, and by releasing cytokines - important mediators of inflammation - which increase cell proliferation and angiogenesis. But apart from higher risk of tumourigenesis due to chronic inflammation, the immune system cells also participate in tumor microenvironment formation. The main contributors are tumor associated macrophages, dendritic cells and T-cells. Besides other things, the complex tumor microenvironment is characterized by the presence of many inflammation mediators which assist in malignant cell proliferation, tumour progression and metastasis and angiogenesis. This bachelor thesis describes the key protumor and antitumor factors which are also involved in the inflammation process. These factors include proinflammatory cytokines, enzymes and transcription factors. The transcription factor NF-κB plays an...
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Circadian regulation of STAT3 protein in the SCN and it's activation by leptin in the SCN, other parts of hypothalamus and the pineal gland
Moníková, Veronika ; Bendová, Zdeňka (advisor) ; Jelínková, Dana (referee)
JAK/STAT signaling pathway is one of the most studied intracellular cascades transmitting signals from the extracellular environment to the cell nucleus in order to affect expression of target genes. Circadian clocks localized in the suprachiasmatic nuclei (SCN) of the hypothalamus are sensitive especially to light but they can respond to non-photic stimuli such as growth factors, opioids, leptin and cytokines that have been demonstrated to perform its function via the JAK/STAT signaling pathway. The recent findings of our laboratory demonstrated that STAT3 protein is highly produced by SCN of rat. Primary aim of our experiments was to test the circadian regulation of STAT3 production in SCN and describe the effect of exogenously administered leptin on STAT3 phosphorylation in the SCN, pineal gland and hypothalamic structures responsible for regulated feeding behavior and energy metabolism. Because activation of leptin receptors may stimulate a number of other signaling cascades, we chose phosphorylated forms of kinase ERK1/2 and GSK-3β as other markers of intracellular changes after administration of leptin in the studied structures. Our results proved rhythmic production of STAT3 protein in SCN of rat and indicated circadian regulation of sensitivity to leptin in hypothalamic structures. The data...
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Role of STAT3 signalling in oncogenesis and cancer therapy
Machalová, Veronika ; Hodný, Zdeněk (advisor) ; Brábek, Jan (referee)
STAT3 (Signal Transducer and Activator of Transcription 3) is considered to be one of the possible targets of cancer treatment. The ability of STAT3 constitutive activation to form tumors is a foundation of such theories. Additionally, constitutively activated STAT3 is present in many types of cancer with high occurrence, such as breast and prostate carcinoma. This protein is required in normal body cells as well. STAT3 is a transcription factor targeting many genes that are essential for the cell. STAT3 is activated by phosphorylation of its tyrosine residue and homodimerization. Proteins transcribed with help of STAT3 function in cell cycle progression, cell growth, replication, negative regulation of apoptosis, and other roles, typical for cancer. Moreover, STAT3 is modulating mitochondrial function and maintaining ROS production in mitochondria, but in form of transcriptionally inactive monomers. The purpose of this Thesis is to review known data about STAT3 in oncogenesis and by that, to show STAT3 has great potential to become the target of cancer treatment. This Thesis contains a short overview of known STAT3 inhibitors as well. Key words: Signal Transducer and Activator of Transcription 3 (STAT3), JAK/STAT3 pathway, constitutive activation, cancer, tumor, inhibitor, mitochondria, apoptosis
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