NFATc1 und p53 in der epithelial-mesenchymalen Transition des Pankreaskarzinoms
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Philipps-Universität Marburg
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Abstract
The ductal adenocarcinoma of the pancreas is one of the most aggressive solid tumor entities. The dismal prognosis of PDAC is primarily caused by the early formation of distant metastases.
The nuclear factor of activated T-cells (NFAT) c1 is an oncogenic transcription factor that is expressed both in advanced PanIN lesions and in invasive pancreatic cancer and was identified as a central player in the progression of PDACs. Importantly, the oncogenic potential of NFATc1 is significantly determined by the inactivation of the tumorsuppressor p53.
The main focus of this thesis is the elucidation of the mechanism and the functional consequences of antithetical NFATc1- and p53-signaling in the regulation of the oncogenic transcription factor SOX 2. NFATc1 induces SOX 2 transcription by direct enhancer binding, while p53 posttranscriptionally inhibits the activity of SOX 2 by inducing the expression of SOX 2-targeting microRNAs. The imbalance of these two mechanisms, for example in context of p53-inactivation or as a consequence of constitutive NFATc1 activation in pancreatic cancer cells leads to an increased expression of SOX 2 and results in the induction of epithelial to mesenchymal transition programs by consecutive transcriptional activation of ZEB 1, TWIST 1 and SNAI 1. Epithelial to mesenchymal transition (EMT) increases the motility and invasive capacities of PDAC cells and facilitates the formation of distant metastases. Since NFATc1-SOX 2-dependent pancreatic cancer progression occurs upon TP53 mutation and deletion, not the gain-of-function mutation, but the inactivation of tumorsuppressive p53 activity is required for full-blown activity of the NFATc1-SOX 2-axis.
The identification of the hierarchial network of antithetical pathways that influence pancreatic cancer cell plasticity might reveal novel therapeutic strategies for pancretic cancer treatment.
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Dates
Created: 2017Issued: 2017-02-23Updated: 2017-02-23
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
Keywords
metastasisSOX2NFATc1epithelial-mesenchymal transitionpancreatic cancerNFATc1EMT
DFG-subjects
BauchspeicheldrüsenkrebsMetastaseProtein p53Medizin
DDC-Numbers
610
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Völker, Nadine: NFATc1 und p53 in der epithelial-mesenchymalen Transition des Pankreaskarzinoms. : Philipps-Universität Marburg 2017-02-23. DOI: https://doi.org/10.17192/z2017.0143.