Oncotarget

Research Papers:

The ratio of STAT1 to STAT3 expression is a determinant of colorectal cancer growth

Harini Nivarthi, Claire Gordziel, Madeleine Themanns, Nina Kramer, Markus Eberl, Björn Rabe, Michaela Schlederer, Stefan Rose-John, Thomas Knösel, Lukas Kenner, Patricia Freund, Fritz Aberger, Xiaonan Han, Robert Kralovics, Helmut Dolznig, Susanne Jennek, Karlheinz Friedrich, Richard Moriggl _

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Oncotarget. 2016; 7:51096-51106. https://doi.org/10.18632/oncotarget.9315

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Abstract

Harini Nivarthi1,2, Claire Gordziel3, Madeleine Themanns1,4, Nina Kramer5, Markus Eberl6, Björn Rabe7, Michaela Schlederer1,8, Stefan Rose-John7, Thomas Knösel9, Lukas Kenner1,8, Patricia Freund1,4, Fritz Aberger6, Xiaonan Han10, Robert Kralovics2, Helmut Dolznig5, Susanne Jennek3, Karlheinz Friedrich3, Richard Moriggl1,4

1Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria

2CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

3Institute of Biochemistry II, University Hospital Jena, Jena, Germany

4Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Medical University of Vienna, Vienna, Austria

5Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria

6Department of Molecular Biology, University of Salzburg, Salzburg, Austria

7Biochemical Institute, Christian-Albrechts-University Kiel, Kiel, Germany

8Clinical Institute of Pathology, Medical University of Vienna, University of Veterinary Medicine Vienna, Vienna, Austria

9Institute of Pathology, Ludwig-Maximilians-University Munich, Munich, Germany

10Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA

Correspondence to:

Richard Moriggl email: richard.moriggl@lbicr.lbg.ac.at

Keywords: STAT1, STAT3, colorectal cancer

Received: October 02, 2015     Accepted: April 10, 2016     Published: May 12, 2016

ABSTRACT

The role of STAT1 and STAT3 for colorectal carcinoma (CRC) development and progression is controversial. We evaluated 414 CRC patient samples on tissue microarrays for differential expression of STAT1 and STAT3 protein levels and correlated ratios with clinical parameters. Concomitant absence of nuclear STAT1 and STAT3 expression was associated with significantly reduced median survival by ≥33 months (p=0.003). To gain insight into underlying mechanisms, we generated four CRC cell lines with STAT3 knockdown. The cell lines harbor different known mutational drivers and were xenografted into SCID mice to analyze the influence of STAT3 on their tumor growth behavior. Experimental downregulation of STAT3 expression had differential, cell-line specific effects on STAT1 expression levels. STAT1 consistently showed nuclear localization irrespective of its tyrosine phosphorylation status. Two characteristic STAT1/3 expression patterns with opposite growth behavior could be distinguished: cell lines with a low STAT1/high STAT3 ratio showed faster tumor growth in xenografts. In contrast, xenografts of cell lines showing high STAT1 and low STAT3 levels grew slower. Importantly, these ratios reflected clinical outcome in CRC patients as well. We conclude that the ratio of STAT1 to STAT3 expression is a key determinant of CRC progression and that STAT1 counteracts pro-tumorigenic STAT3 signaling. Thus, we suggest that the STAT3/STAT1 ratios are better clinical predictors in CRC as compared to STAT3 or STAT1 levels alone.


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