MicroRNA-125a influences breast cancer stem cells by targeting leukemia inhibitory factor receptor which regulates the Hippo signaling pathway

Oncotarget. 2015 Jul 10;6(19):17366-78. doi: 10.18632/oncotarget.3953.


Cancer stem cells (CSC) are the main driving force behind cancer initiation and progression. The molecular mechanisms that regulate CSC properties are poorly understood. MicroRNAs (miRNAs) play a significant role in normal and cancer tissues. Here, we show that miRNA-125a indirectly regulates TAZ, an effector molecule in the Hippo pathway, through the leukemia inhibitory factor receptor (LIFR). The miR-125a→LIFR axis affected the homeostasis of nonmalignant and malignant breast epithelial stem cells through the Hippo signaling pathway. Inhibition of miR-125a in breast cancer cells led to a significant reduction in the CSC pool. In contrast, enhanced expression of miR-125a in nonmalignant breast epithelial cells resulted in significant expansion of the stem cell pool. Gain of function and loss of function of LIFR directly correlated with the inhibition and overexpression of miR-125a, respectively. Modulation of miR-125a led to a change in the activity of TAZ and its subcellular localization. We further demonstrated that miR-125a influenced stem cells by regulating Hippo signaling through LIFR in human primary breast cancer cells confirming the data obtained from established cell lines. We suggest that miR-125a could be a potential target against CSCs that maybe used along with the existing conventional therapies.

Keywords: Hippo signaling; LIFR; breast cancer; miR-125a; stem cells.

MeSH terms

  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Female
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Gene Expression Regulation, Neoplastic / genetics*
  • Hippo Signaling Pathway
  • Humans
  • Immunoblotting
  • Leukemia Inhibitory Factor Receptor alpha Subunit / biosynthesis*
  • Leukemia Inhibitory Factor Receptor alpha Subunit / genetics
  • MicroRNAs / biosynthesis*
  • MicroRNAs / genetics
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology*
  • Polymerase Chain Reaction
  • Protein Serine-Threonine Kinases / metabolism*
  • Signal Transduction / physiology
  • Transfection


  • LIFR protein, human
  • Leukemia Inhibitory Factor Receptor alpha Subunit
  • MIRN125 microRNA, human
  • MicroRNAs
  • Protein Serine-Threonine Kinases