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

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.

SUBMITTER: Nandy SB

PROVIDER: S-EPMC4627314 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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

Nandy Sushmita Bose SB Arumugam Arunkumar A Subramani Ramadevi R Pedroza Diego D Hernandez Keziah K Saltzstein Edward E Lakshmanaswamy Rajkumar R

Oncotarget 20150701 19

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 c ...[more]

PMID: 25962054

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Project description:To date, the role of hematopoietic-substrate-1-associated protein X-1 (HAX1) in liver cancer is rarely studied. The present study explored the role of HAX1 in liver cancer. The association between HAX1 expression and survival of patients with liver cancer was analyzed by a log-rank test. The target genes for HAX1 was predicted by TargetScan and verified by a dual-luciferase reporter assay. The protein and mRNA expressions of HAX1 in liver cancer and adjacent non-cancerous tissues were examined by immunohistochemistry and reverse transcription-quantitative PCR (RT-qPCR). The transfection efficiency of HAX1, small interfering RNA against HAX1, microRNA (miR)-125a mimics, miR-125a inhibitor, miR-223 mimics and miR-223 inhibitor in liver cancer cells was determined by RT-qPCR. The expression of HAX1, p53, VEGF, epithelial-to-mesenchymal transition (EMT)-related markers (E-cadherin, N-cadherin and vimentin) in the cancer cells were determined by western blotting and RT-qPCR. Cell viability, migration, invasion and colony formation rates were determined by Cell Counting Kot-8, wound healing, Transwell and colony formation assays, respectively. The results showed that high expression of HAX1 in liver cancer was found relate to poor prognosis in patients with liver cancer, and upregulation of HAX1 expression in liver cancer tissues was related to lower overall survival. miR-125a-5p directly binds to HAX1. Upregulation of miR-125a-5p expression inhibited cell viability, migration, invasion and colony formation of SK-Hep1 cells and reduced the expression of HAX1, VEGF, N-cadherin and vimentin, but increased cell apoptosis and the expression of p53 and E-cadherin. However, the effects miR-125a-5p upregulation were partially reversed by SK-Hep1 cells with HAX1 overexpression. Downregulated miR-125a-5p in SNU-387 cells produced opposite effects, which was partially reversed by HAX silencing. In conclusion, miR-125a-5p suppresses liver cancer growth via targeting HAX1 and concurrently modulating the expression of p53 and VEGF and EMT-related markers.

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

Publications

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

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