Auswirkungen des MEN1 Gens auf den Apoptose Signalweg in pankreatischen neuroendokrinen Neoplasien

Die multiple endokrine Neoplasie Typ 1 (MEN1) ist eine seltene autosomal dominant vererbte Tumorerkrankung. Eine inaktivierende Keimbahnmutation des MEN1-Gens (Chromosom 11q13), welches als Tumorsuppressorgen fungiert, löst die Erkrankung aus. Patienten, die von MEN1 betroffen sind, entwickeln neuro...

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Bibliographic Details
Main Author: Wagener, Nele
Contributors: Buchholz, Malte (Prof. Dr. ) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2021
Online Access:PDF Full Text
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Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant disease, which is caused by a mutation of the tumor suppressor gene MEN1 located at chromosome 11q13 by the Patients affected by MEN1 develop neuroendocrine tumors, typically primary hyperparathyroidism, pituitary adenomas and gastro-enteropancreatic neuroendocrine neoplasia. Some patients may also develop bronchial and thymus carcinoids, as well as adenomas of the adrenal gland. A high mortality rate of MEN1 patients is due to duodenopancreatic neuroendocrine tumors and the thymus carcinoids and, so far, there are no therapeutic approaches to stop the progression of the disease. The exact and complete function of the menin has not been fully elucidated yet. To date, there has been no study clarifying the role of menin in the apoptosis signal path. Apoptosis is a programmed cell death, initiated by caspase-8 and carried out by the executioner caspases 3/7. The caspase 8 and 3/7 activities measurement were carried out in the two neuroendocrine cell lines (BON1, QGP1), the human pancreatic stellate cells HPSC2.2 and the mouse embryo fibroblasts after induction of apoptosis mediated by the treatment with staurosporine. The MEN1 gene was knocked down by MEN1 siRNA. After induction of apoptosis, it could be shown that the activity was significantly down-regulated after menin was knocked down. Real-time qPCR was able to show that an intact MEN1 allele upregulates the gene expression of TP53 and CDKN1A. MEN1 knockdown caused a down-regulation of the TP53 and CDKN1A gene expression as well as a significant difference of the caspase-8 and 3/7 activity between MEN1 wildtyp and knockdown/knockout. In summary, the results suggest that menin exerts an influence on the apoptosis signaling pathway. Knock-down/knock-out of MEN1 interferes with the activity of caspases, thus disturbing the apoptotic process. These new insights could highlight new therapeutic approaches in the MEN1 patients.