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Dr. Jekyll and Mr. Hyde in liver cancer

(Vienna, 28 April 2011) The protein Stat3 is known to promote tumour growth. A team of researchers at MedUni Vienna headed by Wolfgang Mikulits have now discovered in liver cancer that Stat3 is also responsible for suppressing the tumour, however. The surprising discovery of this duality of Stat3 as an oncogene or tumour suppressor is of major importance for cancer research.

Hepatocellular carcinoma (HCC) is one of the world’s most common and most aggressive forms of cancer. It is widespread in Asia and Africa in particular but is also occurring increasingly in the Western hemisphere because of metabolic diseases such as the inflammatory “fatty liver” or infections with hepatitis C. With HCC tumour development, the protein Stat3 is usually activated and has therefore been viewed as an oncogene for a long time.

Researchers reveal Mr. Hyde as Dr. Jekyll
In this regard it was surprising for Wolfgang Mikulits and his team that a tumour-suppressing effect of Stat3 was observed for the first time in HCC cells. The tests showed in detail that the properties of Stat3 in HCC cells depend on the protein p14ARF.
Together with p14ARF Stat3 takes on its carcinogenic form, without p14ARF it suppresses tumour formation. If both are missing there will therefore also be rapid tumour development. So the presence of p14ARF is decisive for whether Stat3 has a positive or negative effect on liver cancer. This could also be important for other types of cancer.

New forms of therapy necessary
The results of this study therefore show clear possibilities of improving the therapeutic strategies for liver cancer. Based on the results, recognising p14ARF-negative and p14ARF-positive HCC patients is particularly important for targeted Stat3 therapy.
Treatment aimed at Stat3 could have a fatal and opposite effect in p14ARF-negative HCC patients. There is increased tumour growth because the tumour suppressor function of Stat3 is therefore prevented.


Participating scientists:
This study funded by the Austrian Science Fund (FWF) as part of the “Jak-Stat” special research programme was carried out in the working group of Ao. Univ. Prof. Mag. Dr. Wolfgang Mikulits from the Cancer Research Institute in Department of Medicine I at MedUni Vienna in close cooperation with Univ. Doz. Dr. Richard Moriggl from the Ludwig Boltzmann Institute for Cancer Research and Dr. Robert Eferl, Cancer Research Institute in Department of Medicine I at MedUni Vienna and at the Ludwig Boltzmann Institute for Cancer Research, and also Dr. Sebastian Nijman from the Centre of Molecular Medicine (CEMM). As lead authors Dr. Doris Schneller, Mag. Georg Machat and Alexandra Sousek from the working group of Wolfgang Mikulits contributed to this study.

The described work is published in the international top journal “Hepatology”.

Publication in „Hepatology“:
» “p19ARF/p14ARF controls oncogenic functions of Stat3 in hepatocellular carcinoma”
Doris Schneller, Georg Machat, Alexandra Sousek, Verena Proell, Franziska van Zijl, Gudrun Zulehner, Heidemarie Huber, Markus Mair, Markus K. Muellner, Sebastian M.B. Nijman, Robert Eferl, Richard Moriggl and Wolfgang Mikulits.
Hepatology. 2011 Mar 30. doi: 10.1002/hep.24329. [Epub ahead of print]