Nandy Sushmita Bose, Arumugam Arunkumar, Subramani Ramadevi, Pedroza Diego, Hernandez Keziah, Saltzstein Edward, Lakshmanaswamy Rajkumar
Center of Excellence in Cancer Research, Department of Biomedical Sciences MSB1, El Paso, Texas, USA.
Graduate School of Biomedical Sciences, El Paso, Texas, USA.
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.
癌症干细胞(CSC)是癌症起始和进展的主要驱动力。调控CSC特性的分子机制目前仍知之甚少。微小RNA(miRNA)在正常组织和癌组织中发挥着重要作用。在此,我们表明miRNA - 125a通过白血病抑制因子受体(LIFR)间接调控Hippo通路中的效应分子TAZ。miR - 125a→LIFR轴通过Hippo信号通路影响非恶性和恶性乳腺上皮干细胞的稳态。在乳腺癌细胞中抑制miR - 125a导致CSC库显著减少。相反,在非恶性乳腺上皮细胞中增强miR - 125a的表达导致干细胞库显著扩大。LIFR的功能获得和功能丧失分别与miR - 125a的抑制和过表达直接相关。miR - 125a的调节导致TAZ活性及其亚细胞定位的改变。我们进一步证明,miR - 125a通过在人原发性乳腺癌细胞中通过LIFR调节Hippo信号来影响干细胞,这证实了从已建立的细胞系中获得的数据。我们认为miR - 125a可能是针对CSC的潜在靶点,可与现有的传统疗法联合使用。