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Funktionelle Charakterisierung des putativen Tumorsuppressors "Epithelial Membrane Protein 3"

Christians, Arne

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Abstract

EMP3 has been proposed as a potential tumor suppressor gene in neuroblastomas, gliomas and other solid tumors, due to its differential methylation and expression pattern. In these tumors EMP3 is often transcriptionally silenced by promoter hypermethylation. The biological function of EMP3 itself is largely unknown. Based on homologies to other members of the protein family, it was presumed that EMP3 is involved in the regulation of proliferation, apoptosis and cell-cell-interactions. The aim of this work is the functional characterization of EMP3 and its role in glioma formation and progression. To this end we analyzed the methylation and expression pattern of EMP3 in gliomas, non-neoplastic tissues and cell lines. In addition we studied the effects of RNA-interference-mediated knockdown of EMP3 on proliferation, migration and apoptosis in an in vitro cancer cell line model. Furthermore we utilized different interaction assays to identify novel protein-protein interaction partners of EMP3. EMP3 is expressed in almost all analyzed normal tissues, with the highest levels in leukocytes, neurons and astrocytic cells. In gliomas, the EMP3 protein levels are highest in glioblastomas, of which over 80% show very strong EMP3 expression, while in low-grade gliomas only 20% show elevated levels of EMP3. High levels of EMP3 also correlate with shorter progression-free and overall patient survival. RNA-interference-mediated repression of EMP3 significantly reduces the proliferation and migration of cancer cells in vitro and increased their susceptibility to induced cell death. This is in part caused by decreased phosphorylation and activation of the EGFR, AKT and ERK signaling kinases. EMP3 is part of a complex interaction and signaling network, of which we could identify 10 novel interacting proteins. Through this network EMP3 is possibly involved in the regulation of several important signaling and trafficking pathways. EMP3 is therefore likely to be a mediator and regulator of intracellular trafficking and signal transduction. The data support a role for EMP3 in the progression of cancer, but, at least in glioma, not as a tumor suppressor. Nevertheless EMP3 could be a valid prognostic and possibly even predictive biomarker in the diagnosis of glioma as well as a potential novel therapeutic target in different tumors and other diseases.

Item Type: Dissertation
Supervisor: Wiemann, Prof. Dr. Stefan
Date of thesis defense: 10 December 2014
Date Deposited: 18 Dec 2014 06:57
Date: 2014
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 500 Natural sciences and mathematics
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