Medizinische Universität Graz - Research portal
Selected Publication:
Seidl, C.
Interactions of miR-183 cluster and the hedgehog signaling pathway in cisplatin-resistant NSCLC cells.
[ Diplomarbeit/Master Thesis (UNI) ] University of Graz; 2018. pp.74.
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- Authors Med Uni Graz:
- Advisor:
- Hrzenjak Andelko
- Panzitt Katrin
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- Abstract:
- Lung cancer is a leading cause of cancer deaths worldwide and platinum-based chemotherapy (e.g. cisplatin) is frequently the treatment of choice. However, resistance to cisplatin is a major issue and contributes to the high mortality rate. In our previous studies different miRNAs were found deregulated in cisplatin-resistant (CisR) compared to cisplatin-sensitive, parental (Par) NSCLC cells. Especially miR-183 cluster, which was markedly deregulated in CisR cells, is of high interest, as it was connected to bad survival rates in lung cancer patients. miRNAs are known to target the mRNA of their target genes, leading to downregulation of target proteins. These can be proteins within cancer related pathways like the Hedgehog-signaling pathway (Hh), which is mainly active in embryonic development and often reactivated in cancer cells. It is partially described that members of the Hh-signaling pathway are upregulated in CisR cells. Therefore, we investigated whether deregulation of miR-183 cluster is influencing Hh-signaling and resulting in altered sensitivity of H460-CisR lung cancer cells to cisplatin. In H460-Par cells miR-183 cluster inhibition led to higher protein expression of the Gli proteins, the key players of the Hh-signaling pathway. We also observed that upregulation of miR-183 cluster in H460-CisR cells resulted in lower Gli-protein expression. Further, a direct interaction of one miR-183 cluster member, miR-182-5p, and Gli2 was found. Moreover, our results have shown that the cell proliferation and colony forming ability of H460-CisR cells were reduced after miR-183 cluster upregulation. These findings give a strong indication that the miR-183 cluster is affecting the Hh-signaling pathway, resulting in decreased resistance in cisplatin-resistant NSCLC cells. The direct connection between the Hh-signaling pathway and cisplatin-resistance in lung cancer has to be further investigated to proof the potential clinical relevance for NSCLC patients.