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Inhibition of STAT3^Tyr705 Phosphorylation by Smad4 Suppresses Transforming Growth Factor β–Mediated Invasion and Metastasis in Pancreatic Cancer Cells

Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center, San Antonio, Texas

Requests for reprints: James W. Freeman, Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900. Phone: 210-567-5298; Fax: 210-567-6687; E-mail: freemanjw{at}uthscsa.edu.

Key Words: transforming growth factor β • Smad4 • epithelial-mesenchymal transition • STAT3 • pancreatic cancer

The role of Smad4 in transforming growth factor β (TGFβ)–mediated epithelial-mesenchymal transition (EMT), invasion, and metastasis was investigated using isogenically matched pancreatic cancer cell lines that differed only in expression of Smad4. Cells expressing Smad4 showed an enhanced TGFβ-mediated EMT as determined by increased expression of vimentin and decreased expression of β-catenin and E-cadherin. TGFβ-mediated invasion was suppressed in Smad4-intact cells as determined by in vitro assays, and these cells showed a reduced metastasis in an orthotopic model of pancreatic cancer. Interestingly, TGFβ inhibited STAT3^Tyr705 phosphorylation in Smad4-intact cells. The decrease in STAT3^Tyr705 phosphorylation was linked to a TGFβ/Smad4-dependent and enhanced activation of extracellular signal-regulated kinases, which caused an increase in serine phosphorylation of STAT3^Ser727. Down-regulating signal transducer and activator of transcription 3 (STAT3) expression by short hairpin RNA in Smad4-deficient cells prevented TGFβ-induced invasion. Conversely, expressing a constitutively activated form of STAT3 (STAT3-C) in Smad4-intact cells enhanced invasion. This study indicates the requirement of STAT3 activity for TGFβ-induced invasion in pancreatic cancer cells and implicates Smad4-dependent signaling in regulating STAT3 activity. These findings further suggest that loss of Smad4, leading to aberrant activation of STAT3, contributes to the switch of TGFβ from a tumor-suppressive to a tumor-promoting pathway in pancreatic cancer. [Cancer Res 2008;68(11):4221–8]

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