AbstractsBiology & Animal Science

The Role of Gtl2 in Hepatocarcinogenesis

by Eva Christina Zeller

Institution: Universität Tübingen
Year: 2015
Record ID: 1102294
Full text PDF: http://hdl.handle.net/10900/62857


Carcinogenesis is a progressive multistep progress comprising various genetic alterations such as mutations in tumor suppressor genes and oncogenes. Non-genotoxic carcinogens (NGC) induce tumor formation by mechanisms other than changes in the underlying DNA sequence. Phenobarbital (PB) is a classic non-genotoxic carcinogen leading to perturbations in gene expression and DNA methylation. In mice, PB selects for Ctnnb1 (encoding β-catenin) mutated liver tumors. Recently, non-coding RNAs from the Dlk1 Dio3 cluster were identified as potential biomarkers for mouse liver tumor promotion caused by PB. One gene within this imprinted region is named Gtl2/ Meg3. We could show that Gtl2 expression was elevated in mice treated with substances of the PB type like PCB 153 and conazole funizides. But the transferability of the biomarker potential of Gtl2 to rats was limited. Using a switchable Gtl2 expressing hepatoma cell line, we found out that the expression of several microRNAs, immune system genes and olfactory receptors were altered with enforced Gtl2 expression. A supposable mechanism to regulate olfactory receptor and immune system gene expression could be via the polycomb repressive complex 2. Due to the lack of an appropriate Gtl2 knockout mouse model, Gtl2 was constitutively overexpressed in murine liver by the use of adenoviral Gtl2. There, Gtl2 was found to regulate cell cycle genes. No final decision could be made whether Gtl2 serves as a tumor suppressor as proposed in literature or as a tumor promoter suggested by members of the MARCAR consortium. There were supports for both characteristics. An initiation promotion study in a mouse constitutively overexpressing Gtl2 would help to answer this question. The second part of this work was to generate a glutamine synthetase (GS) gene expression “atlas” in a GS reporter mouse, which indirectly predicts in which organs/ cells Wnt signaling is active. Most GS promoter activity was found in brain, liver, kidney, testis and heart. In addition, the growth of GS positive liver tumors was pursued non-invasively in the GS reporter mouse by MRI, whereas PET failed to visualize small GS positive liver tumors.; Karzinogenese ist einen fortschreitender, mehrstufiger Prozess, der verschiedene genetische Veränderungen wie Mutationen in Tumorsuppressorgenen und Onkogenen umfasst. Nicht-genotoxische Karzinogene (NGC) induzieren die Tumorbildung durch Mechanismen ohne die zugrundeliegende DNA Sequenz zu verändern. Phenobarbital (PB) ist ein klassischer Vertreter der nicht-genotoxischen Karzinogene, das zu Veränderungen in der Genexpression und DNA Methylierung führt. In Mäusen selektiert PB für Ctnnb1 (codiert für β-Catenin) mutierte Lebertumore. Kürzlich wurden nicht-kodierende RNAs aus dem Dlk1-Dio3 Cluster als potentielle Biomarker für Lebertumore der Maus identifiziert, die durch PB verursacht wurden. Ein Gen innerhalb dieser imprinteten Region ist Gtl2/ Meg3. Wir konnten zeigen, dass die Gtl2 Expression in Mäusen erhöht war, die mit Substanzen des PB Typs wie PCB 153 und Conazol…