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Type of publication: Journal Article
Type of document: Full Paper

Year: 2016

Authors: Nivarthi, H; Gordziel, C; Themanns, M; Kramer, N; Eberl, M; Rabe, B; Schlederer, M; Rose-John, S; Knösel, T; Kenner, L; Freund, P; Aberger, F; Han, X; Kralovics, R; Dolznig, H; Jennek, S; Friedrich, K; Moriggl, R

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

Source: Oncotarget. 2016; 7(32):51096-51106

Authors Vetmeduni Vienna:

Freund Patricia
Kenner Lukas
Moriggl Richard
Themanns Madeleine

Vetmed Research Units
Institute of Pathology, Pathology of Laboratory Animals
Institute of Animal Breeding and Genetics, Unit for Functional Cancer Genomics

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.

Keywords Pubmed: Animals
Biomarkers, Tumorgenetics
Caco-2 Cells
Cell Line, Tumor
Cell Proliferationgenetics
Colorectal Neoplasmsdiagnosisgeneticspathology
Gene Expression Regulation, Neoplastic
HCT116 Cells
HT29 Cells
Mice, SCID
STAT1 Transcription Factorgenetics
STAT3 Transcription Factorgenetics

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