c-MYC Proliferation Überexpression application/pdf The role of PRMT1 overexpression in pancreatic ductal adenocarcinoma ppn:356629864 Gli1, anchorage-independent growth doctoralThesis 2015 Philipps-Universität Marburg urn:nbn:de:hebis:04-z2015-01551 2015-03-09 Bauchspeicheldrüsenkrebs Das Ziel dieser Arbeit war die Untersuchung der Rolle von PRMT1 im humanen duktalen Adenokarzinom des Pankreas. Ausgangspunkt hierzu war eine Veröffentlichung, die eine Überexpression von PRMT1 auf Transkriptebene im PDAC relativ zu gesundem Gewebe zeigte. Als erste Aufgabe wurde in der vorliegenden Arbeit der Frage nachgegangen, ob auch eine Erhöhung der Proteinspiegel von PRMT1 im PDAC-Gewebe vorliegt. Durch Vorarbeiten im Labor und im Rahmen dieser Arbeit konnte diese Fragestellung durch immunhistochemische Färbungen von Pankreasschnitten positiv beantwortet werden. Um eine potenzielle Funktion dieser verstärkten PRMT1-Expression im PDAC zu untersuchen, wurde die Proliferationsfähigkeit der PDAC-Zelllinien Panc1 und MiaPaCa2 mittels Wachstumskurven bestimmt. Durch siRNA-vermittelte Depletion von PRMT1 in diesen Zellen wurde deutlich, dass das Protein für die Proliferationsfähigkeit essenziell ist. Diese Erkenntnis ließ sich durch eine Wiederholung des Experiments in HeLa-Zellen auch auf weitere Tumorzellen ausweiten. Zudem wurde die Fähigkeit von PDAC-Zellen zum ankerunabhängigen Wachstum in Soft-Agar-Assays untersucht. Nach Depletion von PRMT1 war diese Fähigkeit gehemmt. In einem weiteren Teil dieser Arbeit wurden zuvor erbrachte Ergebnisse der Arbeitsgruppe bezüglich einer Assoziation des Transkriptionsfaktors GLI1 mit PRMT1 einer Validierung und weiteren Bearbeitung unterzogen. Mit Hilfe von Expressionsanalysen auf Transkriptebene konnten keine belastbaren Hinweise auf einen Einfluss von PRMT1 auf die GLI1-Spiegel festgestellt werden. Eine Interaktion der beiden Proteine konnte weder in vivo noch in vitro nachgewiesen werden und eine Methylierung von GLI1 durch PRMT1 konnte nicht abschließend verifiziert werden. Eine Rolle von PRMT1 bei der Koaktivierung der GLI1-abhängigen Genexpression bleibt fraglich und bedarf weiterer Untersuchungen. Dem Transkriptionsfaktor c-MYC wurde in Veröffentlichungen eine steigernde Wirkung auf die Expressionsrate von PRMT1 im Zuge von Entwicklungsprozessen nachgewiesen. In der vorliegenden Arbeit wurde geprüft, ob dieser Mechanismus auch in Zellen des PDAC existiert. Mit Hilfe von c-MYC-Depletionen konnte bestätigt werden, dass in diesem System ebenfalls eine Regulation der Expression von PRMT1 durch c-MYC sowohl auf Transkript- als auch auf Proteinebene stattfindet. Durch Hybridisierung eines Oligonukleotid-Microarrays wurde der Einfluss von PRMT1 auf das Transkriptom von Panc1-PDAC-Zellen analysiert. Von den 51 erhaltenen Kandidatengenen, die unter siRNA-vermittelter PRMT1-Depletion mehr als zweifach in ihrer Expression reguliert waren, konnten bisher zwei Gene validiert werden. Für die Proteine GLIPR1 und ANXA8, die von diesen Genen kodiert werden, wurden in verschiedenen Publikationen bereits tumorrelevante Funktionen nachgewiesen. Die weitere funktionelle Charakterisierung dieser Proteine im PDAC wird eine der Aufgaben im künftigen Verlauf des Projekts sein. Molekularbiologie und Tumorforschung This thesis aimed to analyze the role of PRMT1 in human pancreatic ductal adenocarcinoma (PDAC). Given that overexpression of PRMT1 has been reported to occur on transcript level in PDAC relative to healthy tissue, it was investigated here whether an increase of PRMT1 expression in PDAC tissue is also detectable on protein level. Immunohistochemical stainings revealed increased protein levels of PRMT1 in tumor cells as well as tumor stroma cells of the PDAC. In order to study a potential biological function of this elevated PRMT1 expression in PDAC, the proliferative capacity of the PDAC cell lines Panc1 and MiaPaCa2 was determined using growth curve assays. siRNA-mediated depletion of PRMT1 in these cells revealed an essential function of the protein for the replicative capacity. A similar growth disadvantage due to PRMT1 depletion was also observed in HeLa cells. Furthermore, the ability of PDAC cells to grow without anchorage was measured in soft agar assays. In conditions with PRMT1 depletion, this ability was inhibited. In another part of this thesis, data previously generated in the group regarding an association of the transcription factor GLI1 with PRMT1 were validated and further investigated. Expression analyses did not show compelling evidence for an influence of PRMT1 on GLI1 transcript levels. An interaction of the two proteins could not be confirmed in vivo or in vitro and methylation of GLI1 by PRMT1 was not conclusively verified. A role of PRMT1 in the coactivation of GLI1-dependent gene expression remains doubtful and needs additional research. In the literature, it has been shown that the transcription factor c-MYC activates the transcription of the PRMT1 gene in the course of developmental processes. In this work, the existence of this connection was studied in PDAC cells. Using depletion analysis of c-MYC, it was found that PRMT1 expression is enhanced by c-MYC on transcript as well as on protein level. The influence of PRMT1 on the transcriptome of Panc1 PDAC cells was analyzed by oligonucleotide microarray-based gene expression profiling of PRMT1-depleted versus controldepleted cells. So far, two of the 51 candidate genes that were more than twofold regulated upon siRNA-mediated PRMT1 depletion could be validated. 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Richard, Arginine methylation inhibits the binding of proline-rich ligands to Src homology 3, but not WW, domains., The Journal of Biological Chemistry. 275 (2000) 16030–6. ths Prof.Dr. Bauer Uta-Maria Bauer, Uta-Maria (Prof.Dr.) Die Rolle der Überexpression von PRMT1 im duktalen Adenokarzinom des Pankreas Immuncytochemie c-MYC Microarray monograph 2015-02-09 Arginin-Methyltransferase PRMT1 opus:5974 German Arginin-Methyltransferase Medizin ankerunabhängiges Wachstum Zeller, Marc Zeller Marc Gli1 Medical sciences Medicine Medizin https://archiv.ub.uni-marburg.de/diss/z2015/0155/cover.png