Stat3-coordinated Lin-28-let-7-HMGA2 and miR-200-ZEB1 circuits initiate and maintain oncostatin M-driven epithelial-mesenchymal transition

Oncogene. 2013 Nov 7;32(45):5272-82. doi: 10.1038/onc.2012.573. Epub 2013 Jan 14.


Inflammation can act as a crucial mediator of epithelial-to-mesenchymal transition (EMT). In this study, we show that oncostatin M (OSM) is expressed in an autocrine/paracrine fashion in invasive breast carcinoma. OSM stimulation promotes spontaneous lung metastasis of MCF-7 xenografts in nude mice. A conspicuous epigenetic transition was induced by OSM stimulation not only in breast cancer cell lines but also in MCF-7 xenografts in nude mice. The expression of miR-200 and let-7 family members in response to OSM stimulation was downregulated in a signal transducer and activator of transcription factor 3 (Stat3)-dependent manner, resulting in comprehensive alterations of the transcription factors and oncoproteins targeted by these microRNAs. Inhibition of Stat3 activation or the ectopic expression of let-7 and miR-200 effectively reversed the mesenchymal phenotype of breast cancer cells. Stat3 promotes the transcription of Lin-28 by directly binding to the Lin-28 promoter, resulting in the repression of let-7 expression and concomitant upregulation of the let-7 target, high-mobility group A protein 2 (HMGA2). Knock down of HMGA2 significantly impairs OSM-driven EMT. Our data indicate that downregulation of let-7 and miR-200 levels initiates and maintains OSM-induced EMT phenotypes, and HMGA2 acts as a master switch of OSM-induced EMT. These findings highlight the importance of Stat3-coordinated Lin-28B-let-7-HMGA2 and miR-200-ZEB1 circuits in the cytokine-mediated phenotypic reprogramming of breast cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Down-Regulation
  • Epithelial-Mesenchymal Transition / genetics
  • Epithelial-Mesenchymal Transition / physiology*
  • Female
  • Gene Knockdown Techniques
  • HMGA2 Protein / biosynthesis
  • HMGA2 Protein / genetics
  • Heterografts
  • Homeodomain Proteins
  • Humans
  • Inflammation
  • Kruppel-Like Transcription Factors
  • Lung Neoplasms / secondary
  • MCF-7 Cells
  • Mammary Neoplasms, Animal / metabolism
  • Mice
  • Mice, Inbred BALB C
  • MicroRNAs / biosynthesis
  • MicroRNAs / metabolism*
  • Neoplasm Transplantation
  • Oncostatin M / biosynthesis
  • Oncostatin M / metabolism*
  • Promoter Regions, Genetic
  • RNA-Binding Proteins / biosynthesis
  • RNA-Binding Proteins / genetics
  • STAT3 Transcription Factor / metabolism*
  • Up-Regulation
  • Zinc Finger E-box-Binding Homeobox 1


  • HMGA2 Protein
  • Homeodomain Proteins
  • Kruppel-Like Transcription Factors
  • Lin-28 protein, mouse
  • MicroRNAs
  • Mirn200 microRNA, mouse
  • RNA-Binding Proteins
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • ZEB1 protein, mouse
  • Zinc Finger E-box-Binding Homeobox 1
  • mirnlet7 microRNA, mouse
  • Oncostatin M