Abstract
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.
Highlights
Chemoresistance and recurrence of cancers are attributed to a small population of cells within the cancers, designated as cancer stem cells (CSCs) [1,2]
We further demonstrated that miR-125a influenced stem cells by regulating Hippo signaling through leukemia inhibitory factor receptor (LIFR) in human primary breast cancer cells confirming the data obtained from established cell lines
In our previous studies of breast cancer occurrence, we found that miR-125a was upregulated in high risk breast epithelial stem cells compared to low risk groups [5]
Summary
Chemoresistance and recurrence of cancers are attributed to a small population of cells within the cancers, designated as cancer stem cells (CSCs) [1,2]. MicroRNAs are negative regulators of genes, which repress expression at the post-transcriptional level They regulate various properties of CSCs, including self-renewal, differentiation, proliferation, and fate determination, by affecting several key signaling pathways at the molecular level [3]. Dysregulation of the phosphorylation status of Hippo signaling effectors, especially TAZ, has been associated with enhanced selfwww.impactjournals.com/oncotarget renewal and proliferative capabilities of stem cells, leading to a pro-carcinogenic environment [7,8]. These findings prompted us to examine the role of miR-125a in malignant breast epithelial stem cells, and determine its influence on Hippo signaling by altering LIFR expression
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