Abstract #LB-185: The effects of Stat5 deficiency on liver pathogenesis in an inflammatory liver cancer mouse model
Authors: Katrin Friedbichler, Jan-Wilhelm Kornfeld, Susanne Haindl, Tricia Behling, Lukas Kenner, Ken Snibson, Andrey Kozlov, Richard Moriggl
Journal: Cancer Research (2009)

Most cases of human hepatocellular carcinoma (HCC) are a complication of either a chronic hepatic viral infection or liver cirrhosis. Additional risk factors for malignant transformation of hepatocytes include toxins and drugs (e.g. alcohol, aflatoxins, and anabolic steroids), metabolic liver diseases, nonalcoholic fatty liver disease (NAFLD), and diabetes. Transformation is supposed to be dependent on an increased liver cell turnover which is a consequence of a multistep process comprising chronic liver injury and regeneration associated with inflammation and oxidative DNA damage. Patient studies indicate important roles for glucocorticoid and growth hormone (GH) signaling in HCC progression. Signal transducer and activator of transcription 5 (Stat5) is a direct downstream effector molecule of the GH signaling pathway. The transcription factor Stat5 modulates gene expression also by interacting with the glucocorticoid receptor (GR). Linking the above mentioned signaling pathways, Stat5 might be a very promising molecular target for future therapy of liver cancer. The aim of this study is to evaluate the roles of Stat5 in liver GH signaling and tumor formation in vivo. Therefore, a mouse model for inflammatory liver cancer (growth hormone transgenic mice; GHtg mice) was intercrossed with conditional knockout mice lacking hepatic Stat5 and GR (\#916;Stat5 and \#916;GR, using AlfpCre). Body weights of the mice were measured over a time span of thirty-two weeks and liver/body weight ratios and tumor formation were analyzed at four different time points. The study revealed that Stat5 is absolutely required for postnatal body growth. In contrast, the lack of GR seemed to be compensated by GH over-expression, even though a large number of genes responsible for body growth have been shown to be co-regulated by Stat5 and the GR. Surprisingly, the tumor phenotype seen in GHtg mice (tumor formation at approximately eleven months) could not be alleviated by the removal of the down-stream player Stat5. On the contrary, the number and size of tumor foci was increased in GHtg\#916;Stat5 mice with a four months shorter latency. This phenotype was accompanied by an increased fat deposition in the liver already starting at a very young age. GHtg mice deficient in GR, on the other hand, exhibited the same behavior as GHtg controls in all aspects of analysis. These results suggest an additive role of a metabolic syndrome caused by deletion of hepatic Stat5 to the formation of HCC in an inflammatory liver cancer model. Consequently, permanent tissue damage caused by metabolic dysfunction may be a predisposition for HCC which can easily arise in case of additional inflammatory events. On this account, GHtg\#916;Stat5 mice provide a suitable model to study hepatocarcinogenesis, which closely reflects the human pathogenesis of HCC. This mouse model can be of major relevance for translational research and future drug testing.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-185.