Stat Activation in Liver Fibrosis and Late Stage Hepatocarcinogenesis
NETWORK CONTRIBUTION
We investigate the role of Stat3 in hepatic fibrosis and liver carcinoma progression and focus on Stat3 as the molecular link between these different but related liver diseases. Advanced hepatocellular systems combined with animal tumour models allow us to analyse the impact of Stat3 activation in these pathophysiological changes of both parenchymal and mesenchymal compartments. In particular, we employ the epithelial to mesenchymal transition (EMT) of hepatocytes as a close
in vitro correlate of liver carcinoma progression and metastasis. Studies on epithelial-mesenchymal interactions further address the involvement of Stat3 in the communication between malignant hepatocytes and stromal cells of the tumour microenvironment, and thus deal with the molecular and cellular implications of Stat3 activation in the tumour-host crosstalk.
Key Hypothesis:
- Stat3 is the molecular link between hepatic fibrosis and liver carcinoma progression. Other important signal transduction pathways like TGF-ß/PGDF/PI3K/Ras and/or ß-catenin signalling might co-operate with Stat3 activation in tumourigenesis.
Report on funding period 1 (03/2006-03/2010)
SFB-P06WM: Stat Activation in Liver Fibrosis and Late Stage Hepatocarcinogenesis (Wolfgang Mikulits)
We focused on the role of Stat3 in the epithelial to mesenchymal transition (EMT) of malignant hepatocytes, which is an important event during hepatocellular carcinoma (HCC) progression. Advanced cellular hepatic models derived from p19ARF-/- mice combined with in vivo animal tumor models have been established and employed to analyze the pathophysiological impact of Stat3 activation. Stat3Δhc/p19ARF-/- mice have been generated in order to study the impact of Stat3 in hepatocellular EMT.
We found that Stat3 is dispensable for the EMT of p19ARF-/- hepatocytes in vitro, since functionally differentiated Stat3Δhc/p19ARF-/- mice hepatocytes expressing oncogenic Ras displayed transdifferentiation to a fibroblastoid phenotype upon treatment with transforming growth factor (TGF)-beta. Interestingly, p19ARF-/- hepatocytes expressing oncogenic Ras in combination with constitutive active (ca) Stat3 mutants showed reduced tumor growth and metastasis whereas expression of dominant negative (dn) Stat3 versions resulted in enhanced tumor progression. In contrast, expression of caStat3 in Ras-transformed hepatocytes transgenic for the cytoplasmic tail of the oncogenic c-Met receptor and expressing wild type p19ARF, exhibited a tumor-promoting role of Stat3 as expected from the literature. These data suggest that Stat3 might be operative either in a tumor-suppressive or tumor-promoting fashion in neoplastic hepatocytes depending on p19ARF. In addition, Stat3 has been found to be induced by ILEI, the latter representing a novel cytokine that stimulates hepatocytes to EMT in cooperation with oncogenic Ras and that acts downstream of TGF-beta.
Proposal for funding period 2 (03/2010-03/2013)
SFB-P06WM (Wolfgang Mikulits) The pro- and anti-oncogenic role of Stat3 in hepatocellular carcinoma progression
WM contributes to the Research Area ‘JakStat in Cancer and Immune Surveillance’ and focuses on the role of Stat3 during the epithelial to mesenchymal transition (EMT) and tumor progression of hepatocellular carcinoma (HCC). SFB-P06WM showed in funding period 1 that Stat3 suppresses Ras-mediated HCC development in the context of p19ARF deficiency, which suggests a role of Stat3 as a tumor suppressor in hepatocarcinogenesis. Advanced mouse and newly established human models of HCC progression will allow to investigate the molecular interplay between Stat3 and p19ARF as well as to identify further possible interactions between Stat3 and the tumor suppressors Rb or PTEN. Overall, the experimental setting aims to translate data on Stat3 function obtained in mouse models to human HCC progression by the use of human cellular tumor models and available HCC patient samples. Thus, the proposed project of SFB-P06WM will significantly contribute to the understanding of the pro- and anti-oncogenic functions of Stat3 during human cancer progression. In addition, SFB-P06WM will provide novel immortalized hepatocytes derived from Stat3 and Stat5 modified mice to the Technology Platform “Advanced Tissue Culture Models”.
CONTACT
Department of Medicine I, Division: Institute of Cancer Research,
Medical University of Vienna
Broschke-Gasse 8a
A-1090 Vienna
wolfgang.mikulits@meduniwien.ac.at
phone: +43(0)1 4277 65250
fax: +43(0)1 4277-65239
