Implication of STAT3 signaling in human colonic cancer cells during intestinal trefoil factor 3 (TFF3) -- and vascular endothelial growth factor-mediated cellular invasion and tumor growth.
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.
Rivat
Christine
C
Institut National de la Sante et de la Recherche Medicale U482, Hôpital Saint-Antoine, Paris, France. rivat@st-antoine.inserm.fr
Christine
Rivat
R
Rodrigues
Sylvie
S
Sylvie
Rodrigues
R
Bruyneel
Erik
E
Erik
Bruyneel
B
Piétu
Geneviève
G
Geneviève
Piétu
P
Robert
Amélie
A
Amélie
Robert
R
Redeuilh
Gérard
G
Gérard
Redeuilh
R
Bracke
Marc
M
Marc
Bracke
B
Gespach
Christian
C
Christian
Gespach
G
Attoub
Samir
S
Samir
Attoub
A
D017209:Apoptosis; D001483:Base Sequence; D002455:Cell Division; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology*; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D009077:Mucins / Q000502:physiology*; D009124:Muscle Proteins / Q000502:physiology*; D009361:Neoplasm Invasiveness; D010455:Peptides; D020033:Protein Isoforms / Q000502:physiology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000502:physiology*; D000071165:Trefoil Factor-3; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
D017931:DNA Primers; D004268:DNA-Binding Proteins; D009077:Mucins; D009124:Muscle Proteins; D010455:Peptides; D020033:Protein Isoforms; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C082495:TFF3 protein, human; D015534:Trans-Activators; D000071165:Trefoil Factor-3; D042461:Vascular Endothelial Growth Factor A