MicroRNA-125a influences breast cancer stem cells by targeting leukemia inhibitory factor receptor which regulates the hippo signaling pathway
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Sushmita Bose Nandy1, Arunkumar Arumugam1, Ramadevi Subramani1, Diego Pedroza2, Keziah Hernandez1, Edward Saltzstein3 and Rajkumar Lakshmanaswamy1,2
1 Center of Excellence in Cancer Research, Department of Biomedical Sciences MSB1, El Paso, Texas, USA
2 Graduate School of Biomedical Sciences, El Paso, Texas, USA
3 Sadie and Annabelle Garbar Breast Care Center, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, El Paso, Texas, USA
Rajkumar Lakshmanaswamy, email:
Keywords: breast cancer, stem cells, miR-125a, LIFR, hippo signaling
Received: December 15, 2014 Accepted: April 08, 2015 Published: April 29, 2015
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.
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