Src Kinases Mediate STAT Growth Pathways in Squamous Cell Carcinoma of the Head and Neck

Xi, Sichuan; Zhang, Qing; Dyer, Kevin F.; Lerner, Edwina C.; Smithgall, Thomas E.; Gooding, William E.; Kamens, Joanne; Grandis, Jennifer R.

doi:10.1074/jbc.m303499200

Cited by 161 publications

(160 citation statements)

References 56 publications

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“…In HNSCC cells, c-Src was proposed to be a downstream target of the EGFR, as treatment of cells with the EGFR inhibitor ZD1839 was found to block activation of the c-Src pathway (Yang et al, 2004). Src family kinases were also shown to be involved in mediating activation of STATs 3 and 5 in concert with the EGFR in HNSCC cells (Xi et al, 2003). This evidence for a functional association between EGFR and Src/cortactin pathways prompted us to examine EGFR levels in our TMAs.…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of cortactin levels in head and neck squamous cell carcinoma: comparison with epidermal growth factor receptor status

et al. 2008

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Cortactin is an actin-binding Src substrate involved in cell motility and invasion. In this study, we sought to examine the prognostic importance of cortactin protein expression in head and neck squamous cell carcinoma (HNSCC). To do so, cortactin and EGF receptor (EGFR) expression was retrospectively evaluated by immunohistochemistry in a tissue microarray composed of 176 HNSCCs with a mean follow-up time of 5 years. Cortactin immunoreactivity was weak to absent in normal epithelial tissue. Overexpression of the protein in 77 out of 176 tumours (44%) was associated with more advanced tumour-node-metastasis stage and higher histologic grade. Cortactin overexpression was associated with significantly increased local recurrence rates (49 vs 28% for high and low expressing carcinomas, respectively), decreased disease-free survival (17 vs 61%), and decreased the 5-year overall survival of (21 vs 58%), independently of the EGFR status. In multivariate analysis, cortactin expression status remained an independent prognostic factor for local recurrence, disease-free survival, and overall survival. Importantly, we identified a subset of patients with cortactin-overexpressing tumours that displayed low EGFR levels and a survival rate that equalled that of patients with tumoral overexpression of both EGFR and cortactin. These findings identify cortactin as a relevant prognostic marker and may have implications for targeted therapies in patients with HNSCC.

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Section: Discussionmentioning

confidence: 99%

Prognostic significance of cortactin levels in head and neck squamous cell carcinoma: comparison with epidermal growth factor receptor status

et al. 2008

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“…The same assembly involving STAT3 and ap85 requires a direct interaction between the SH2 domains of the PI3-K regulatory subunit and the Y656 tyrosine of STAT3 which itself interacts with the IFNg cytokine receptor through its SH2 domain (Pfeffer et al, 1997). Furthermore, the EGFR was shown to interact with src tyrosine kinase at Y891 and Y920 (Xi et al, 2003) and to associate with the cadherin-catenin complex through direct interaction between b-catenin and the EGFR cytoplasmic tail (Hoschuetzky et al, 1994). Consistent with this model, b-catenin is found hyperphosphorylated in STAT3-Y705F-transformed HCT8/S11 cells.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2004

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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.

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“…Whole-cell extracts were prepared and EMSAs performed on 4% native polyacrylamide gels as described (Wong et al, 1994;Xi et al, 2003). STAT3 activation was evaluated by using binding reactions with 20 mg of extracted protein, and radiolabeled high-affinity serum-inducible element (hSIE) duplex oligonucleotide was used to clone and characterize After 10 days when the tumors were clearly palpable (approximately 2 mm in maximum diameter), mice were randomly assigned to treatment groups (STAT3 decoy, mutant control decoy, ciplatin alone, cisplatin plus STAT3 decoy, cisplatin plus mutant control decoy).…”

Section: Electrophoretic Mobility Shift Assaymentioning

confidence: 99%

In vivo antitumor efficacy of STAT3 blockade using a transcription factor decoy approach: implications for cancer therapy

2004

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The development of more effective prevention and treatment strategies for solid tumors is limited by an incomplete understanding of the critical growth pathways that are activated in carcinogenesis. Signal transducers and activators of transcription (STAT) proteins have been linked to transformation and tumor progression. Several approaches have been used to block STAT3 in cancer cells resulting in reduced proliferation and apoptosis. We tested the hypothesis that blocking STAT3 activation using a transcription factor decoy approach would decrease tumor growth and STAT3 target gene expression in vivo. In a xenograft model of squamous cell carcinoma of the head and neck (SCCHN), daily administration of the STAT3 decoy (25 lg) resulted in decreased tumor volumes, abrogation of STAT3 activation, and decreased expression of STAT3 target genes (VEGF, Bcl-xL, and cyclin D1) compared to treatment with a mutant control decoy. Blockade of STAT3 with the STAT3 decoy also induced apoptosis and decreased proliferation, an effect that was augmented when the STAT3 decoy was combined with cisplatin, both in vitro and in vivo. These results suggest that a transcription factor decoy approach may be used to target STAT3 in cancers that demonstrate increased STAT3 activation including SCCHN. Oncogene (2005) 24, 970-979.

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Src Kinases Mediate STAT Growth Pathways in Squamous Cell Carcinoma of the Head and Neck

Cited by 161 publications

References 56 publications

Prognostic significance of cortactin levels in head and neck squamous cell carcinoma: comparison with epidermal growth factor receptor status

Prognostic significance of cortactin levels in head and neck squamous cell carcinoma: comparison with epidermal growth factor receptor status

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

In vivo antitumor efficacy of STAT3 blockade using a transcription factor decoy approach: implications for cancer therapy

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