Signal transducers and activators of transcription 3 (STAT3) directly regulates cytokine-induced fascin expression and is required for breast cancer cell migration

J Biol Chem. 2011 Nov 11;286(45):38886-93. doi: 10.1074/jbc.M111.286245. Epub 2011 Sep 20.

Abstract

The cytokines oncostatin M (OSM) and IL-6 promote breast cancer cell migration and metastasis. Both cytokines activate STAT3, a member of the STAT (signal transducers and activators of transcription) family of transcription factors. Through transcriptional regulation of its target genes, STAT3 controls a wide range of cellular processes, including cellular proliferation, oncogenesis, and cancer metastasis. Fascin is an actin-bundling protein involved in cell migration. Elevated levels of fascin expression are found in many metastatic cancers, and inhibition of fascin function by small chemical compounds leads to a block of tumor metastasis. In this work, we demonstrate that fascin is a direct STAT3 target gene in response to OSM and IL-6 in both mouse and human breast cancer cells. We show that NFκB also binds to the fascin promoter in response to cytokine treatment and this binding is STAT3-dependent. Both STAT3 and NFκB are required for the cytokine-induced expression of fascin in cancer cells. Furthermore, we demonstrate that STAT3, in directly controlling fascin expression, is both necessary and sufficient for breast cancer cell migration.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Carrier Proteins / biosynthesis*
  • Carrier Proteins / genetics
  • Cell Line, Tumor
  • Cell Movement*
  • Cell Proliferation / drug effects
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Interleukin-6 / metabolism*
  • Interleukin-6 / pharmacology
  • Mammary Neoplasms, Animal / genetics
  • Mammary Neoplasms, Animal / metabolism*
  • Mice
  • Microfilament Proteins / biosynthesis*
  • Microfilament Proteins / genetics
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Neoplasm Metastasis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Oncostatin M / metabolism*
  • Oncostatin M / pharmacology
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*

Substances

  • Antineoplastic Agents
  • Carrier Proteins
  • IL6 protein, human
  • Interleukin-6
  • Microfilament Proteins
  • NF-kappa B
  • Neoplasm Proteins
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Stat3 protein, mouse
  • Oncostatin M
  • fascin