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Philipps-Universität Marburg
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Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the malignancies with the poorest
prognosis. While the most common mutation in PDAC cells occurs in the KRAS gene,
there are several other signaling pathways that are regularly affected, including the
Hedgehog (Hh) signaling pathway. In canonical Hh-signaling the binding of a ligand
leads to the activation of the transcription factors GLI1, GLI2, and GLI3 in the cell
nucleus. In the nucleus the GLI-proteins can either induce or repress the transcription of
Hh target genes. GLI3 can achieve both outcomes depending on wether it undergoes
proteasomal cleavage (known as processing) after its translation. This process is
initiated by protein kinase A (PKA) and converts the transcriptional activator GLI3FL
into the repressor GLI3R. As a result, GLI3 can have opposing roles, but the repressor
form is particularly known for its potent effect on transcription. However, there is still
limited research on the role of GLI3 in malignant conditions. That is why this work
examines the effect that GLI3 has in PDAC cells and explores ways to influence the
protein and its modification to inhibit proliferation.
The study found that PDAC cell lines express relatively low levels of GLI3, but its
subcellular localization remains unaffected. However, it was observed that GLI3FL
constantly shuttles between the nucleus and cytoplasm and is degraded faster in the
cytoplasm of epithelial PDAC cell lines compared to other cells. Furthermore, the study
confirmed the potent effect of GLI3 by showing that both the introduction of exogenous
GLI3R as well as the depletion of endogeneous GLI3 can significantly inhibit
proliferation. The knockout also provided evidence that GLI3 expression affects
epithelial-mesenchymal transition (EMT), a process associated with increased
metastasis and invasion in tumor cells. Since primary cilia play a crucial role in the Hh
signaling pathway and are predominantly absent in PDAC cells, the study investigated
the mechanism underlying the absence of cilia. It was found that inhibiting mTOR, PI3
kinase, and KRASG12D all promote ciliogenesis. Additionally, the rate of ciliated cells
increases with higher confluence in cell culture. However, the formation of GLI3R in
both ciliated and non-ciliated cells could only be slightly stimulated by activation of the
PKA. Therefore, it can be inferred that cilia are not essential for processing and that
processing is impaired in PDAC epithelial cells.The findings from this study contribute to a better understanding of the characteristics
and effects of GLI3 and further establish it as an attractive therapeutic target in PDAC
treatment.
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Dates
Created: 2025Issued: 2025-08-06Updated: 2025-08-06
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
Keywords
Tumorproliferation und EMTPankreaskarzinom/Pancreatic Ductal Adenocarcinoma (PDAC)Primärzilium und SignalverarbeitungHedgehog-SignalwegGLI3
DFG-subjects
PankreasHedgehogGLI3Karzinom
DDC-Numbers
610
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Schulte, Nils: Die Rolle von GLI3 in Tumorzellen des Pankreaskarzinoms. : Philipps-Universität Marburg 2025-08-06. DOI: https://doi.org/10.17192/z2025.0337.