Der Einfluss der Zielgene PLAC8 und CIP2A auf die Tumorprogression von malignen Pankreastumoren
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Philipps-Universität Marburg
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Abstract
Pancreatic carcinomas have one of the worst prognoses among tumor diseases. They are usually diagnosed late and offer few therapy options. Due to their heterogeneous clinical appearance, pancreatic neuroendocrine neoplasms (pNEN) pose a challenge in medicine. But even the largest group of pancreatic carcinomas, pancreatic ductal adenocarcinomas (PDAC), push medicine to its limits due to their high mortality.
The aim of this study was to deepen the understanding of both tumor entities and compare them. pNEN and PDAC were juxtaposed using the target genes Cancerous/ cellular inhibitor of protein phosphatase 2A (CIP2A) and Placenta-specific 8 (PLAC8). Both target genes play an important role in the cell cycle regulation of pancreatic carcinomas and many other tumor entities. In this study, a PLAC8 knockout was generated in cells of a pancreatic neuroendocrine tumor (pNET) using CRISPR/Cas9, and alternative constructs were offered. These constructs were modified variants of PLAC8 with different and/or missing sequences. The inability to replace PLAC8 in the cells demonstrates the relevance of unaltered expression of PLAC8 for cell survival. PLAC8 may play a role in the form of an long non-coding RNA. In another study, CIP2A was specifically downregulated in pNET and PDAC cells using TD52. Subsequently, the expression levels of various cell cycle modulators were determined at the RNA and protein levels. These data show that CIP2A plays a key role in tumor progression and regulation, particularly through the regulation of the PI3K/AKT signaling pathway. A comparison of both cell lines revealed some differences, which can be explained by various initiation mutations of pNEN and PDAC. These mutations enable tumor cells to bypass healthy cell cycle regulation and associated apoptosis.
Overall, many similarities and differences between pNEN and PDAC were identified in this study using the cell lines BON1 and S2-007, which can become therapeutically relevant. Both PLAC8 and CIP2A can be used as targets for future therapies, which is why these target genes should continue to be investigated. The pathomechanisms of both tumor entities are not yet fully understood, nor is the role of the target genes examined. This study contributes to the understanding of pancreatic carcinomas.
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Created: 2024Issued: 2025-01-08Updated: 2025-01-08
Faculty
Medizin
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Philipps-Universität Marburg
Language
ger
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DoctoralThesis
Keywords
pankreatisch enodkrine NeoplasiePLAC8PDACpNENCIP2ACIP2APDACpancreatic enodrine neoplasiapankreatisch duktales AdenokarzinomPankreaskarzinomePancreatic carcinomapNENPLAC8pancreatic ductal adenocarcinoma
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610
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Kogelheide, Malena: Der Einfluss der Zielgene PLAC8 und CIP2A auf die Tumorprogression von malignen Pankreastumoren. : Philipps-Universität Marburg 2025-01-08. DOI: https://doi.org/10.17192/z2024.0388.