Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Kothmaier, H.
Untersuchungen zur differenziellen Proteinexpression und Inhibition beim Malignen Pleuralen Mesotheliom.
[ Dissertation ] Graz Medical University; 2008. pp.106.
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- Autor*innen der Med Uni Graz:
- Kothmaier Hannelore
- Betreuer*innen:
- Popper Helmuth
- Smolle-Juettner Freyja-Maria
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- Abstract:
- Malignant pleural mesothelioma (MPM) is an asbestos-related tumour difficult to detect early and treat effectively. Asbestos causes genetic modifications and cell signalling events that favour the resistance of MPM to apoptosis and chemotherapy. Only a small number of patients, approximately 10%, survive more than 3 years. The aim of the previous study was to assess possible differences within signalling pathways between short-term survivors (survival <3 years; STS) and long-term survivors (survival >3 years; LTS) of MPM. In order to do this, proteins engaged in cell signalling pathways, enforcing proliferation, anti-apoptosis, angiogenesis, and other cellular activities were investigated by to identify proteins which might be relevant targets for therapeutic intervention. Hence this PCNA (proliferating cell nuclear antigen) was selected for inhibition experiments. Small inhibitory RNAs (siRNAs) were applied targeting PCNA in mesothelioma cell lines. Knockdown of PCNA by siRNA led to down regulation of PCNA protein expression and mRNA expression as shown by Western blot-and Gene expression microarray analysis. The results suggest on the one hand that PCNA maybe influence telomerase reverse transcriptase (hTERT) and exonuclease1 (hEXO1) expression, and on the other hand that PCNA, hTERT, and hEXO1 were regulated by a common mechanism, not known yet. Epidermal growth factor receptor (EGFR) is expressed stronger in LTS whereas platelet derived growth factor receptor (PDGFR) signalling is more abundant in STS. It is of interest that both, EGFR and PDGFR, induce PCNA expression. Taking this into account, the results further imply that PCNA expression benefits from EGFR and/or PDGFR activation in LTS and STS. Blocking key proteins acting within several signalling pathways might be potential targets for further translational approaches in MPM. PCNA alone or in combination with EGFR or PDGFR could be one of these targets. The study provides novel insights into the regulatory mechanisms of signalling pathways in MPM, which differentially promote tumour growth in LTS and STS.