title: The ratio of STAT1 to STAT3 expression is a determinant of colorectal cancer growth.
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.
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Harini
authors.initials: H
authors.lastname: Nivarthi
authors.affiliation: Institute of Biochemistry II, University Hospital Jena, Jena, Germany.
authors.forename: Claire
authors.initials: C
authors.lastname: Gordziel
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Medical University of Vienna, Vienna, Austria.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Themanns
authors.affiliation: Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: Nina
authors.initials: N
authors.lastname: Kramer
authors.affiliation: Department of Molecular Biology, University of Salzburg, Salzburg, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Eberl
authors.affiliation: Biochemical Institute, Christian-Albrechts-University Kiel, Kiel, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Rabe
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Clinical Institute of Pathology, Medical University of Vienna, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Michaela
authors.initials: M
authors.lastname: Schlederer
authors.affiliation: Biochemical Institute, Christian-Albrechts-University Kiel, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: Institute of Pathology, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Knösel
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Clinical Institute of Pathology, Medical University of Vienna, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Lukas
authors.initials: L
authors.lastname: Kenner
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Medical University of Vienna, Vienna, Austria.
authors.forename: Patricia
authors.initials: P
authors.lastname: Freund
authors.affiliation: Department of Molecular Biology, University of Salzburg, Salzburg, Austria.
authors.forename: Fritz
authors.initials: F
authors.lastname: Aberger
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Han
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Kralovics
authors.affiliation: Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria.
authors.forename: Helmut
authors.initials: H
authors.lastname: Dolznig
authors.affiliation: Institute of Biochemistry II, University Hospital Jena, Jena, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Jennek
authors.affiliation: Institute of Biochemistry II, University Hospital Jena, Jena, Germany.
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Friedrich
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Medical University of Vienna, Vienna, Austria.
authors.forename: Richard
authors.initials: R
authors.lastname: Moriggl
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics; D018938:Caco-2 Cells; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D011379:Prognosis; D050794:STAT1 Transcription Factor / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
keywords: STAT1; STAT3; colorectal cancer