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Projekt Druckansicht

Inhibition der Fettsäuresynthas, der PI3Kinase/AKT/mTOR und der MAPKinasen in der endokrinen Hepatokrzinogenese bei Ratten

Fachliche Zuordnung Pathologie
Förderung Förderung von 2011 bis 2014
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 201664920
 
Erstellungsjahr 2014

Zusammenfassung der Projektergebnisse

The main purpose of the project was to investigate the significance of the AKT/mTOR pathway, the MAPK pathway and the lipid metabolism in a diabetic rat model of insulin-induced hepatocarcinogenesis resulting from low-dose transplantation of pancreatic islets into the liver, followed by subsequently inhibiting one or a combination of these pathways by administration of specific drugs. We showed that insulin-induced rat hepatocarcinogenesis is the result of a complex deregulation of intracellular signaling as well as dysregulation of cellular metabolism, particular leading to increased lipogenesis. Impaired combined signaling of the AKT/mTOR and Ras/Raf/MAPK pathways has been found to be the main mediator of carcinogenesis, both pathways synergizing to induce a profound activation of oncogenic mTORC1. Inhibition of only one member of the activated lipogenesis complex located downstream of mTOR (e.g. Orlistat treatment on FAS in rats, or knocking down SCD1 in mice) is equally inefficient to suppress carcinogenesis. Similar results were obtained following administration of the only FDA-approved drug, the Raf/MAPK-Inhibitor Sorafenib. Nonetheless, treatment with the dual Pi3Kinase/mTOR in rats showed promising results in short-term experiments. Unfortunately, the treatment was too stressful for a long-term approach in this rat model and could not adequately performed. Thus, we needed to switch to the technique of hydrodynamic gene delivery in mice for further investigations. These experiments were both done in close cooperation with Prof. Xin Chen (San Francisco, USA) and by ourselves, because by using resources from the expiring grant, we were able to transfer this valuable technique into our own lab. In a set of consecutive experiments we have established signatures of altered intracellular carcinogenic signaling that are responsible not only for biologically diverse subtypes of liver tumors but by constituting the driving events, may also define the main types of liver tumors. Thus, we have reached the following additional achievements: - mTORC1 is the primary mediator and thus the main pharmacological target in HCC driven by combined AKT/Ras activity; - only a complete silencing of mTORC1 can overcome harmful feedback mechanisms of drug resistance in HCC with concomitant AKT and Ras activation, - ablation of transcriptional repressor Bmi1 delays AKT/Ras induced hepatocarcinogenesis, - deregulation of DNA-dependent protein kinase catalytic subunit contributes to HCC development, - the AKT pathway contributes to p53 dysregulation in p53 non-mutated HCC, - combined overexpression of mutant ß-catenin and oncoprotein YAP is the molecular hallmark of human hepatoblastomas and leads to hepatoblastoma development in mice, - YAP induces NOTCH in human HCC via transcriptional regulation of the Jagged1 ligand, and - that NOTCH and combined AKT/NOTCH signaling are important mediators and targets of different types of cholangiocarcinogenesis. This last important finding includes the surprising result that cholangiocarcinogenesis can originate in vivo from mature hepatocytes which was conceptually unknown and thus also constitutes an important contribution for understanding tumorous as well as non-tumorous cell plasticity in human livers. The importance of this finding is underscored by a number of editorials on our discovery as well as the publication of several, subsequent studies, confirming our data. Based on this observation, we subsequently have acquired additional preliminary data on the molecular mechanisms leading to NOTCH activation in human cholangiocarcinomas. These findings are the foundation for a prolongation of this grant.

Projektbezogene Publikationen (Auswahl)

 
 

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