Signal transducer and activator of transcription (STAT) 3 is overexpressed or 
activated in most types of human tumors and has been classified as an oncogene. 
In the present study, we investigated the contribution of the STAT3s to the 
proinvasive activity of trefoil factors (TFF) and vascular endothelial growth 
factor (VEGF) in human colorectal cancer cells HCT8/S11 expressing VEGF 
receptors. Both intestinal trefoil peptide (TFF3) and VEGF, but not pS2 (TFF1), 
activate STAT3 signaling through Tyr(705) phosphorylation of both STAT3alpha and 
STAT3beta isoforms. Blockade of STAT3 signaling by STAT3beta, depletion of the 
STAT3alpha/beta isoforms by RNA interference, and pharmacologic inhibition of 
STAT3alpha/beta phosphorylation by cucurbitacin or STAT3 inhibitory peptide 
abrogates TFF- and VEGF-induced cellular invasion and reduces the growth of 
HCT8/S11 tumor xenografts in athymic mice. Differential gene expression analysis 
using DNA microarrays revealed that overexpression of STAT3beta down-regulates 
the VEGF receptors Flt-1, neuropilins 1 and 2, and the inhibitor of DNA 
binding/differentiation (Id-2) gene product involved in the neoplastic 
transformation. Taken together, our data suggest that TFF3 and the essential 
tumor angiogenesis regulator VEGF(165) exert potent proinvasive activity through 
STAT3 signaling in human colorectal cancer cells. We also validate new 
therapeutic strategies targeting STAT3 signaling by pharmacologic inhibitors and 
RNA interference for the treatment of colorectal cancer patients.