A Signal Transducer and Activator of Transcription 3 center dot Nuclear Factor kappa B (Stat3 center dot NF kappa B) Complex Is Necessary for the Expression of Fascin in Metastatic Breast Cancer Cells in Response to Interleukin (IL)-6 and Tumor Necrosis Factor (TNF)-alpha

作者：Snyder Marylynn; Huang Jianyun; Huang Xin Yun; Zhang J Jillian^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2014, 289(43): 30082-30089.

DOI：10.1074/jbc.M114.591719

• Breast Cancer
• Stat3
• Transcription Regulation
• Tumor Metastasis
• Tumor Necrosis Factor (TNF)
• Fascin
• NF KappaB

Background: IL-6/Stat3 promote breast cancer metastasis through regulation of the fascin gene. Results: In addition to IL-6, TNF-alpha induces binding of a Stat3NF kappa B complex to the fascin promoter to induce transcription. Conclusion: Both NF kappa B and Stat3 are required for cytokine-induced fascin expression and cell migration. Significance: Identification of proteins critical for breast cancer metastasis will reveal drug targets.
IL-6 mediated activation of Stat3 is a major signaling pathway in the process of breast cancer metastasis. One important mechanism by which the IL-6/Stat3 pathway promotes metastasis is through transcriptional regulation of the actin-bundling protein fascin. In this study, we further analyzed the transcriptional regulation of the fascin gene promoter. We show that in addition to IL-6, TNF-alpha increases Stat3 and NF kappa B binding to the fascin promoter to induce its expression. We also show that NFB is required for Stat3 recruitment to the fascin promoter in response to IL-6. Furthermore, Stat3 and NFB form a protein complex in response to cytokine stimulation. Finally, we demonstrate that an overlapping STAT/NF kappa B site in a highly conserved 160-bp region of the fascin promoter is sufficient and necessary to induce transcription in response to IL-6 and TNF-alpha.

• 出版日期2014-10-24