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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

¹ Institut National de la Sante et de la Recherche Medicale U482, Hôpital Saint-Antoine, Paris, France; ² Laboratory of Experimental Cancerology, University Hospital, Gent, Belgium; and ³ CEA, Service de Génomique Fonctionnelle, Evry, France

Requests for reprints: Attoub Samir, Institut National de la Sante et de la Recherche Medicale U482, Hôpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France. Phone: 33-1-49284648; Fax: 33-1-44749318; E-mail: rivat{at}st-antoine.inserm.fr

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 Tyr⁷⁰⁵ phosphorylation of both STAT3 and STAT3ß isoforms. Blockade of STAT3 signaling by STAT3ß, depletion of the STAT3/ß isoforms by RNA interference, and pharmacologic inhibition of STAT3/ß 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 STAT3ß 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 VEGF₁₆₅ 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.

Key Words: TFF • neuropilins • VEGFR • Id-2 • cucurbitacin

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