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

// Harini Nivarthi 1, 2 , Claire Gordziel 3 , Madeleine Themanns 1, 4 , Nina Kramer 5 , Markus Eberl 6 , Bjorn Rabe 7 , Michaela Schlederer 1, 8 , Stefan Rose-John 7 , Thomas Knosel 9 , Lukas Kenner 1, 8 , Patricia Freund 1, 4 , Fritz Aberger 6 , Xiaonan Han 10 , Robert Kralovics 2 , Helmut Dolznig 5 , Susanne Jennek 3 , Karlheinz Friedrich 3 , Richard Moriggl 1, 4 1 Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria 2 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria 3 Institute of Biochemistry II, University Hospital Jena, Jena, Germany 4 Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Medical University of Vienna, Vienna, Austria 5 Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria 6 Department of Molecular Biology, University of Salzburg, Salzburg, Austria 7 Biochemical Institute, Christian-Albrechts-University Kiel, Kiel, Germany 8 Clinical Institute of Pathology, Medical University of Vienna, University of Veterinary Medicine Vienna, Vienna, Austria 9 Institute of Pathology, Ludwig-Maximilians-University Munich, Munich, Germany 10 Division 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.