6777

STAT5B

PURPOSE: Signal transducer and activator of transcription 5 (STAT5) is activated in squamous cell carcinoma of the head and neck (SCCHN), where targeting of STAT5 inhibits tumor growth in vitro and in vivo. The role of STAT5 activation in carcinogenesis, tumor progression, and response to therapy remains incompletely understood. In this study, we investigated the effects of STAT5 activation on squamous epithelial carcinogenesis and response to therapy. EXPERIMENTAL DESIGN: The functional consequences of STAT5 activation in squamous epithelial carcinogenesis were examined using cells derived from normal (Het-1A) and transformed mucosal epithelial cells engineered to express constitutive-active mutants of STAT5. RESULTS: The growth rate of stable clones derived from both normal and transformed squamous epithelial cells expressing the constitutive-active STAT5 was increased. In SCCHN xenografts, tumor volumes were increased in constitutive-active STAT5 mutant cells compared with vector-transfected controls. Constitutive activation of STAT5 significantly increased cell migration and invasion through Matrigel, as well as the transforming efficiency of SCCHN cells in vitro, as assessed by soft agar assays. The constitutive-active STAT5 clones derived from SCCHN cells showed changes consistent with an epithelial-mesenchymal transition including decreased expression of E-cadherin and increased vimentin in comparison with control transfectants. In these cells, STAT5 activation was associated with resistance to cisplatin-mediated apoptosis and growth inhibition induced by the epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib. CONCLUSIONS: These results suggest that constitutive STAT5 signaling enhances tumor growth, invasion, and epithelial-to-mesenchymal transition in squamous epithelial carcinogenesis and may contribute to resistance to epidermal growth factor receptor tyrosine kinase inhibitor and chemotherapy.

Active Stat5a/b predicts early recurrence and disease-specific death in prostate cancer (PC), which both typically are caused by development of metastatic disease. Herein, we demonstrate that Stat5a/b induces epithelial-to-mesenchymal transition (EMT) of PC cells, as shown by Stat5a/b regulation of EMT marker expression (Twist1, E-cadherin, N-cadherin, vimentin, and fibronectin) in PC cell lines, xenograft tumors in vivo, and patient-derived PCs ex vivo using organ explant cultures. Jak2-Stat5a/b signaling induced functional end points of EMT as well, indicated by disruption of epithelial cell monolayers and increased migration and adhesion of PC cells to fibronectin. Knockdown of Twist1 suppressed Jak2-Stat5a/b-induced EMT properties of PC cells, which were rescued by re-introduction of Twist1, indicating that Twist1 mediates Stat5a/b-induced EMT in PC cells. While promoting EMT, Jak2-Stat5a/b signaling induced stem-like properties in PC cells, such as sphere formation and expression of cancer stem cell markers, including BMI1. Mechanistically, both Twist1 and BMI1 were critical for Stat5a/b induction of stem-like features, because genetic knockdown of Twist1 suppressed Stat5a/b-induced BMI1 expression and sphere formation in stem cell culture conditions, which were rescued by re-introduction of BMI1. By using human prolactin knock-in mice, we demonstrate that prolactin-Stat5a/b signaling promoted metastases formation of PC cells in vivo. In conclusion, our data support the concept that Jak2-Stat5a/b signaling promotes metastatic progression of PC by inducing EMT and stem cell properties in PC cells.CI - Copyright (c) 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.