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

被引：34

作者：

Nivarthi, Harini ^{[1
,2
]}

Gordziel, Claire ^{[3
]}

Themanns, Madeleine ^{[1
,4
]}

Kramer, Nina ^{[5
]}

Eberl, Markus ^{[6
]}

Rabe, Bjoern ^{[7
]}

Schlederer, Michaela ^{[1
,8
]}

Rose-John, Stefan ^{[7
]}

Knoesel, Thomas ^{[9
]}

Kenner, Lukas ^{[1
,8
]}

Freund, Patricia ^{[1
,4
]}

Aberger, Fritz ^{[6
]}

Han, Xiaonan ^{[10
]}

Kralovics, Robert ^{[2
]}

Dolznig, Helmut ^{[5
]}

Jennek, Susanne ^{[3
]}

Friedrich, Karlheinz ^{[3
]}

Moriggl, Richard ^{[1
,4
]}

机构：

[1] Ludwig Boltzmann Inst Canc Res, Vienna, Austria

[2] Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria

[3] Univ Hosp Jena, Inst Biochem 2, Jena, Germany

[4] Med Univ Vienna, Univ Vet Med Vienna, Inst Anim Breeding & Genet, Vienna, Austria

[5] Med Univ Vienna, Inst Med Genet, Vienna, Austria

[6] Salzburg Univ, Dept Mol Biol, Salzburg, Austria

[7] Univ Kiel, Biochem Inst, Kiel, Germany

[8] Univ Vet Med Vienna, Med Univ Vienna, Clin Inst Pathol, Vienna, Austria

[9] Univ Munich, Inst Pathol, Munich, Germany

[10] Cincinnati Childrens Hosp Med Ctr, Div Gastroenterol Hepatol & Nutr, Cincinnati, OH 45229 USA

来源：

ONCOTARGET | 2016年 / 7卷 / 32期

基金：

奥地利科学基金会;

关键词：

STAT1; STAT3; colorectal cancer; TUMOR PROGRESSION; SIGNAL TRANSDUCER; ACTIVATION; CARCINOMA; MICE; MICROENVIRONMENT; TUMORIGENESIS; REGENERATION; INTERFERON; STRESS;

D O I：

10.18632/oncotarget.9315

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：51096 / 51106

页数：11