Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Gantenbein, N.
Eukaryotic Translation Initiation Factors in Non-Small Cell Lung Cancer
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2018. pp.160.
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- Autor*innen der Med Uni Graz:
- Gantenbein Nadine
- Betreuer*innen:
- Haybäck Johannes
- Neumeister Peter
- Sattler Wolfgang
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- Abstract:
- Non-small cell lung cancer (NSCLC) belongs to the most frequently diagnosed cancer entity and is one of the leading causes of cancer-related death worldwide. NSCLC has two major histological subtypes, adenocarcinoma (ADC) and squamous (SQC) cell carcinoma. The future for patients suffering from NSCLC is dismal, with a 5-year overall survival rate of 15%. Therefore, constant research is needed to provide better care for future patients. Dysregulation of protein synthesis has received considerable attention as a major step in cancer development and progression. Protein synthesis is regulated at multiple stages, including translation of mRNA into proteins. Some studies suggest that ribosomal protein synthesis plays a direct role during tumor-initiation. Eukaryotic initiation factors (eIFs), which ensure the correct 80S ribosome assembly, are crucial to this translation process. eIFs are linked to the MAPK and the mTOR signaling pathways, which have become major targets in cancer therapy. Mutations or deregulated expression of eIFs influence cell growth and proliferation, and contribute to carcinogenesis. The present thesis was based on the hypothesis that eIFs represent potential biomarkers in NSCLC and that specific members contribute to neoplastic growth. Analysis of eIF expression in NSCLC fresh frozen tissue by Western Blot and qRT-PCR showed altered eIF expression for ADC and SQC compared to healthy non-neoplastic tissue. In addition, survival analyses of Affymetrix and TCGA data sets revealed that eIF expression is indeed associated with overall patient survival. Paclitaxel treatment of A549 cells (a cell line representative for ADC) revealed that eIF expression can be modulated by treatment with this chemotherapeutic compound. Following a general expression analysis of different eIFs in NSCLC, I decided to focus on eIF1A and eIF6 because these were clearly predictive for patient survival. Knockdown of eIF1A in A549 and H520 cells reduced proliferation rates. Apoptosis, senescence and polysome profiles were unaffected by eIF1A knockdown and similar to control conditions. The mechanism(s) being responsible for the observed growth defect in response to RNAi are still not clear. eIF6 is overexpressed in NSCLC and associated with worse patient overall survival in ADC. Depletion of eIF6 in A549 and H520 lung cancer cells reduced proliferation and induced apoptosis. This part of my thesis provides mechanistic insights into the consequences of eIF6 depletion on lung cancer cell growth revealing defects in rRNA processing and ribosomal 60S maturation. In conclusion, the data presented in this study demonstrate that some members of the eIF family are significantly upregulated and associated with worse overall survival in NSCLC patients, suggesting an important contribution of eIFs to the development and progression of lung carcinomas. A better understanding of the molecular mechanisms in pulmonary carcinogenesis could facilitate the development of novel treatment strategies.