Stat3 is a negative regulator of intestinal tumor progression in Apc(Min) mice.
OBJECTIVE
The transcription factor signal transducer and activator of transcription 3 (Stat3) has been considered to promote progression and metastasis of intestinal cancers.


METHODS
We investigated the role of Stat3 in intestinal tumors using mice with conditional ablation of Stat3 in intestinal epithelial cells (Stat3(DeltaIEC)).


RESULTS
In the Apc(Min) mouse model of intestinal cancer, genetic ablation of Stat3 reduced the multiplicity of early adenomas. However, loss of Stat3 promoted tumor progression at later stages, leading to formation of invasive carcinomas, which significantly shortened the lifespan of Stat3(DeltaIEC)Apc(Min/+) mice. Interestingly, loss of Stat3 in tumors of Apc(Min/+) mice had no significant impact on cell survival and angiogenesis, but promoted cell proliferation. A genome-wide expression analysis of Stat3-deficient tumors suggested that Stat3 might negatively regulate intestinal cancer progression via the cell adhesion molecule CEACAM1.


CONCLUSIONS
Our data suggest that Stat3 impairs invasiveness of intestinal tumors. Therefore, therapeutic targeting of the Stat3 signaling pathway in intestinal cancer should be evaluated for adverse effects on tumor progression.
Musteanu
Monica
M
Ludwig Boltzmann Institute for Cancer Research, A-1090 Vienna, Austria.
Blaas
Leander
L
Mair
Markus
M
Schlederer
Michaela
M
Bilban
Martin
M
Tauber
Stefanie
S
Esterbauer
Harald
H
Mueller
Mathias
M
Casanova
Emilio
E
Kenner
Lukas
L
Poli
Valeria
V
Eferl
Robert
R
D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002272:Carcinoembryonic Antigen / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009361:Neoplasm Invasiveness; D050796:STAT3 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013997:Time Factors; D051176:beta Catenin / Q000378:metabolism
C495267:CTNNB1 protein, mouse; D002272:Carcinoembryonic Antigen; C486183:Ceacam1 protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D051176:beta Catenin