miRNA-1246 induces pro-inflammatory responses in mesenchymal stem/stromal cells by regulating PKA and PP2A

Oncotarget. 2017 Jul 4;8(27):43897-43914. doi: 10.18632/oncotarget.14915.


The tumor microenvironment (TME) has an impact on breast cancer progression by creating a pro-inflammatory milieu within the tumor. However, little is known about the roles of miRNAs in cells of the TME during this process. We identified six putative oncomiRs in a breast cancer dataset, all strongly correlating with poor overall patient survival. Out of the six candidates, miR-1246 was upregulated in aggressive breast cancer subtypes and expressed at highest levels in mesenchymal stem/stroma cells (MSCs). Functionally, miR-1246 led to a p65-dependent increase in transcription and release of pro-inflammatory mediators IL-6, CCL2 and CCL5 in MSCs, and increased NF-κB activity. The pro-inflammatory phenotype of miR-1246 in MSCs was independent of TNFα stimulations and mediated by direct targeting of the tumor-suppressors PRKAR1A and PPP2CB. In vitro recapitulation of the TME revealed increased Stat3 phosphorylation in breast epithelial (MCF10A) and cancer cells (SK-BR-3, MCF7, T47D) upon incubation with conditioned medium (CM) of MSCs overexpressing miR-1246. Additionally, this stimulation enhanced proliferation of MCF10A cells, increased migration of MDA-MB-231 cells and induced attraction of THP-1 monocytic cells. Our data shows that miR-1246 acts as both key-enhancer of pro-inflammatory responses in MSCs and putative oncomiR in breast cancer, suggesting its influence on cancer-related inflammation and breast cancer progression.

Keywords: NF-kappaB signaling; breast cancer; mesenchymal stem/stromal cell; microRNA; tumor microenvironment.

MeSH terms

  • 3' Untranslated Regions
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / genetics
  • Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Female
  • Gene Expression Regulation*
  • Gene Knockdown Techniques
  • Humans
  • Inflammation / genetics
  • Inflammation / metabolism
  • Mesenchymal Stem Cells / metabolism*
  • MicroRNAs / genetics*
  • NF-kappa B / metabolism
  • Protein Phosphatase 2 / genetics
  • Protein Phosphatase 2 / metabolism*
  • RNA Interference
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / metabolism


  • 3' Untranslated Regions
  • Cyclic AMP-Dependent Protein Kinase RIalpha Subunit
  • MIRN1246 microRNA, human
  • MicroRNAs
  • NF-kappa B
  • PRKAR1A protein, human
  • Tumor Necrosis Factor-alpha
  • Cyclic AMP-Dependent Protein Kinases
  • PPP2CB protein, human
  • Protein Phosphatase 2