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

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 nuc...

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Autores principales: Nivarthi, Harini, Gordziel, Claire, Themanns, Madeleine, Kramer, Nina, Eberl, Markus, Rabe, Björn, Schlederer, Michaela, Rose-John, Stefan, Knösel, Thomas, Kenner, Lukas, Freund, Patricia, Aberger, Fritz, Han, Xiaonan, Kralovics, Robert, Dolznig, Helmut, Jennek, Susanne, Friedrich, Karlheinz, Moriggl, Richard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5239461/
https://www.ncbi.nlm.nih.gov/pubmed/27191495
http://dx.doi.org/10.18632/oncotarget.9315
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author Nivarthi, Harini
Gordziel, Claire
Themanns, Madeleine
Kramer, Nina
Eberl, Markus
Rabe, Björn
Schlederer, Michaela
Rose-John, Stefan
Knösel, Thomas
Kenner, Lukas
Freund, Patricia
Aberger, Fritz
Han, Xiaonan
Kralovics, Robert
Dolznig, Helmut
Jennek, Susanne
Friedrich, Karlheinz
Moriggl, Richard
author_facet Nivarthi, Harini
Gordziel, Claire
Themanns, Madeleine
Kramer, Nina
Eberl, Markus
Rabe, Björn
Schlederer, Michaela
Rose-John, Stefan
Knösel, Thomas
Kenner, Lukas
Freund, Patricia
Aberger, Fritz
Han, Xiaonan
Kralovics, Robert
Dolznig, Helmut
Jennek, Susanne
Friedrich, Karlheinz
Moriggl, Richard
author_sort Nivarthi, Harini
collection PubMed
description 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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spelling pubmed-52394612017-01-24 The ratio of STAT1 to STAT3 expression is a determinant of colorectal cancer growth Nivarthi, Harini Gordziel, Claire Themanns, Madeleine Kramer, Nina Eberl, Markus Rabe, Björn Schlederer, Michaela Rose-John, Stefan Knösel, Thomas Kenner, Lukas Freund, Patricia Aberger, Fritz Han, Xiaonan Kralovics, Robert Dolznig, Helmut Jennek, Susanne Friedrich, Karlheinz Moriggl, Richard Oncotarget Research Paper 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. Impact Journals LLC 2016-05-12 /pmc/articles/PMC5239461/ /pubmed/27191495 http://dx.doi.org/10.18632/oncotarget.9315 Text en Copyright: © 2016 Nivarthi et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Nivarthi, Harini
Gordziel, Claire
Themanns, Madeleine
Kramer, Nina
Eberl, Markus
Rabe, Björn
Schlederer, Michaela
Rose-John, Stefan
Knösel, Thomas
Kenner, Lukas
Freund, Patricia
Aberger, Fritz
Han, Xiaonan
Kralovics, Robert
Dolznig, Helmut
Jennek, Susanne
Friedrich, Karlheinz
Moriggl, Richard
The ratio of STAT1 to STAT3 expression is a determinant of colorectal cancer growth
title The ratio of STAT1 to STAT3 expression is a determinant of colorectal cancer growth
title_full The ratio of STAT1 to STAT3 expression is a determinant of colorectal cancer growth
title_fullStr The ratio of STAT1 to STAT3 expression is a determinant of colorectal cancer growth
title_full_unstemmed The ratio of STAT1 to STAT3 expression is a determinant of colorectal cancer growth
title_short The ratio of STAT1 to STAT3 expression is a determinant of colorectal cancer growth
title_sort ratio of stat1 to stat3 expression is a determinant of colorectal cancer growth
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5239461/
https://www.ncbi.nlm.nih.gov/pubmed/27191495
http://dx.doi.org/10.18632/oncotarget.9315
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