Antagonism of miR-21 Reverses Epithelial-Mesenchymal Transition and Cancer Stem Cell Phenotype through AKT/ERK1/2 Inactivation by Targeting PTEN

Abstract

BackgroundAccumulating evidence suggested that epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) characteristics, both of which contribute to tumor invasion and metastasis, are interrelated with miR-21. MiR-21 is one of the important microRNAs associated with tumor progression and metastasis, but the molecular mechanisms underlying EMT and CSC phenotype during miR-21 contributes to migration and invasion of breast cancer cells remain to be elucidated.Methodology/Principal FindingsIn this study, MDA-MB-231/anti-miR-21 cells were established by transfected hsa-miR-21 antagomir into breast cancer MDA-MB-231 cells. EMT was evaluated by the changes of mesenchymal cell markers (N-cadherin, Vimentin, and alpha-SMA), epithelial cell marker (E-cadherin), as well as capacities of cell migration and invasion; CSC phenotype was measured using the changes of CSC surface markers (ALDH1 and CD44), and the capacity of sphereforming (mammospheres). We found that antagonism of miR-21 reversed EMT and CSC phenotype, accompanied with PTEN up-regulation and AKT/ERK1/2 inactivation. Interestingly, down-regulation of PTEN by siPTEN suppressed the effects of miR-21 antagomir on EMT and CSC phenotype, confirming that PTEN is a target of miR-21 in reversing EMT and CSC phenotype. The inhibitors of PI3K-AKT and ERK1/2 pathways, LY294002 and U0126, both significantly suppressed EMT and CSC phenotype, indicating that AKT and ERK1/2 pathways are required for miR-21 mediating EMT and CSC phenotype.Conclusions/SignificanceIn conclusion, our results demonstrated that antagonism of miR-21 reverses EMT and CSC phenotype through targeting PTEN, via inactivation of AKT and ERK1/2 pathways, and showed a novel mechanism of which might relieve the malignant biological behaviors of breast cancer.

XRCC1 Gene Polymorphisms and miR-21 Expression in Patients with Colorectal Carcinoma

“…Moreover, Sheng et al [26] found that the protein kinase/phosphatase/phosphatidyl-inositol kinase (AKT/PTEN/ PI3K) signaling pathway is intimately linked with many malignant tumors and their progression, drug resistance, immunity, angiogenesis, and metastasis [27,28]. Furthermore, there have been several studies showing that miR-21 has a significant role in regulating the AKT/ PTEN/ PI3K signaling pathway and contributes to the initiation of carcinogenesis, tumor progression, and metastasis [29,30]. Sheng et al [26] reported that the PTEN gene is a direct target gene of miR-21.…”

Nutrition, Nitrogen Requirements, Exercise and Chemotherapy-Induced Toxicity in Cancer Patients. A puzzle of Contrasting Truths?

“…It has also been reported that activation of p70S6 kinase feedback loop inhibits Rictor phosphorylation, resulting in the suppression of Rictor function [83]. As a result, impaired mTORC2 causes a reduction in the phosphorylation of Akt at serine 473, whose phosphorylation is significantly correlated with cancer stemness [84,85]. These studies underline the increased interest in mTORC2 for its implications in tumorigenesis, however [86], they have also stimulated new ideas on the role played by the amino acids, or some of them in particular, on the pathological mechanisms that lead to cancer or to its prevention.…”

MicroRNAs, a subpopulation of regulators, are involved in breast cancer progression through regulating breast cancer stem cells (Review)

“…miR-146a mediates KLF8-induced CSC features by inhibiting the expression of the Numb homolog (NUMB), a Notch signaling inhibitor (19). miR-21 was identified to increase the proportion of BCSCs that expressed the CSC surface biomarkers CD44 + CD242 -and ALDH1 + (20). miR-21 induces the BCSC phenotype through the depletion of phosphatase and tensin homolog and the activation of protein kinase B (AKT) and extracellular signal-related kinase 1/2 (20).…”

“…miR-21 was identified to increase the proportion of BCSCs that expressed the CSC surface biomarkers CD44 + CD242 -and ALDH1 + (20). miR-21 induces the BCSC phenotype through the depletion of phosphatase and tensin homolog and the activation of protein kinase B (AKT) and extracellular signal-related kinase 1/2 (20). miRNA-125a-targeted leukemia inhibitory factor receptor changes the activity of transcriptional co-activator with PDZ-binging motif, an effector molecule in the Hippo pathway, through which miRNA-125a increases the percentage of stem cells in MCF7 cells (21).…”