Disruption of STAT3 signaling leads to tumor cell invasion through alterations of homotypic cell–cell adhesion complexes

Abstract

STAT3 is frequently overexpressed and constitutively activated by tyrosine phosphorylation during malignant transformation. Despite the clear importance of STAT3 in cell proliferation and survival in diverse human cancers, its possible contribution to tumor cell adhesion, motility and invasion remains hypothetical. We therefore compared the transforming properties of STAT3wt, its constitutively activated dimeric form STAT3C, and the dominant negative mutant STAT3-Y705F in human colorectal HCT8/S11 cancer cells. Both STAT3wt and STAT3C exert a permissive action to the proinvasive activity of the scatter factor HGF in HCT8/S11 cells. In contrast, the monomeric and cytoplasmic mutant Y705F induces a constitutive invasive phenotype through Wnt/Rho-independent and EGFR/PI3-kinase-dependent pathways. Accordingly, Y705F decreases cell-cell homotypic adhesions, and increases cell motility and scattering, as well as lamellipodia-type cellular extensions. STAT3-Y705F-transfected HCT8/S11 cells display an increased tyrosine phosphorylation of the cell-cell adhesion regulator bcatenin and its dissociation from the invasion suppressor E-cadherin at cell-cell contacts. Our data imply that both invasion promoter and repressor genes are controlled by the canonical STAT3 transcription pathways. Disruption of this cascade by Y705F reveals the proinvasive potential of altered forms of STAT3 as a persistent signaling adaptor in cytokine/transforming growth factor receptor scaffolds and oncogenic pathways.

Signal Transducer and Activator of Transcription 3 (STAT3) Protein Suppresses Adenoma-to-carcinoma Transition in Apc/+ Mice via Regulation of Snail-1 (SNAI) Protein Stability

“…Overexpression of a dominant negative STAT3 mutant in a CRC cell line was reported to cause down-regulation of E-cadherin (39). Although SNAI is widely known as a suppressor of E-cadherin, our data and another recent report (4) show that its expression is not significantly affected by STAT3 deletion in IEC.…”

Lentivirus-mediated shRNA interference targeting STAT3 inhibits human pancreatic cancer cell invasion

“…Furthermore, disruption of the STAT3 signaling pathway has been reported to suppress cell invasion by decreasing cellcell homotypic adhesions and increasing cell motility and scattering [31] . In the present study, the invasion ability of these cells with a cell invasion assay was examined and found that STAT3 silencing by RNAi in SW1990 cells resulted in a weak level of invasiveness.…”

Suppressor of cytokine signaling 3 (SOCS3) limits damage-induced crypt hyper-proliferation and inflammation-associated tumorigenesis in the colon

“…Mice with interferon gamma-inducible disruption of STAT3 genes in both macrophages and intestinal epithelial cells (IEC) develop enterocolitis (Alonzi et al, 2004). However, STAT3 phosphorylation is constitutively activated in some colon cancer cell lines and in these model systems, STAT3 inhibitors reduce growth and promote apoptosis (Nakamura et al, 2004;Rivat et al, 2004). Recent studies in the AOM/DSS model of colon carcinogenesis indicate a key role of IL-6 and STAT3 in promoting tumor formation and growth (Becker et al, 2004).…”