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Role of RAGE in melanoma development, growth, and progression

Reith, Maike

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Abstract

The receptor for advanced glycation end-products (RAGE) was identified as cell membrane-bound pattern recognition receptor sensing endogenous alarming signals. Previous work revealed the existence of a plethora of RAGE isoforms and of a complex regulatory machinery enabling their controlled expression. While mainly expressed at low levels in healthy tissues, pathological disorders are often connected with increased RAGE expression. Indeed, besides providing evidence for an upregulation of RAGE in melanoma, we demonstrated recently that diminished sRAGE and esRAGE levels serve as prognostic markers, suggesting a differential expression of distinct RAGE variants in malignant melanoma. To date, the functional role of RAGE in melanoma has not been systematically investigated so far.

This study demonstrated an upregulation of AGER transcripts in benign melanocytic nevi in line with a sufficiency of RAGE overexpression in establishing melanoma hallmarks in a melanocytic cell line. In addition, combining gain- and loss-of-function studies with gene expression analysis led to the identification of RAGE as negative regulator of in trans molecules, such as DNA repair proteins, and consequently of genomic integrity in human and mouse. These findings illustrate that the early occurrence of melanoma-associated mutations found in benign melanocytic nevi and the high genomic instability of melanoma cells might be a consequence of dysregulated RAGE expression. Furthermore, the study provided evidence that the observed benefits of a high RAGE expression on melanoma cells,including sustained proliferation, deregulation of cellular energetics, and prolonged survival, also come along with negative effects such as higher vulnerability to exogenous genotoxic insults. Such negative consequences, which might be another issue of the impact of RAGE on genomic integrity, implicate the existence of strategies regulating RAGE functionality in melanoma. As demonstrated in this study, these might not only comprise the control of gene expression but also alternative splicing and subcellular translocation. Indeed, this work showed for the first time that RAGE protein in melanocytes can also be translocated to the nucleus via active cargo transport, and indicated a loss of nuclear RAGE as characteristic of human malignant melanoma. The study further indicated a pathological upregulation of nuclear export proteins as well as a differential expression of RAGE splicing factors as potential mechanisms behind the aberrant compartmentalization of RAGE upon malignant transformation.

Item Type: Dissertation
Supervisor: Umansky, Prof. Dr. Viktor
Date of thesis defense: 9 October 2015
Date Deposited: 06 Nov 2015 09:24
Date: 2016
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 610 Medical sciences Medicine
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