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MicroRNA-708 activation by glucocorticoid receptor agonists regulate breast cancer tumorigenesis and metastasis via downregulation of NF-κB signaling.

著者 Senthil Kumar KJ , Gokila Vani M , Hsieh HW , Lin CC , Liao JW , Chueh PJ , Wang SY
Carcinogenesis.2019 Feb 01 ; ():.
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Therapeutic administration of glucocorticoids (GC) is frequently used as add-on chemotherapy for palliative purposes during breast cancer treatment. Recent studies have shown that glucocorticoid treatment induces microRNA-708 in ovarian cancer cells, resulting in impaired tumor cell proliferation and metastasis. However, the regulatory functions of glucocorticoids on miR-708 and its downstream target genes in human breast cancer cells (BCCs) are poorly understood. In this study, we found that treatment with either the synthetic glucocorticoid Dexamethasone (DEX) or the natural glucocorticoid mimic, Antcin A (ATA) significantly increased miR-708 expression by transactivation of glucocorticoid receptor alpha (GRα) in MCF-7 and MDA-MB-231 human BCCs. Induction of miR-708 by glucocorticoid receptor (GR) agonists resulted in inhibition of cell proliferation, cell-cycle progression, cancer stem cell-like phenotype and metastasis of BCCs. In addition, GR agonist treatment or miR-708 mimic transfection remarkably inhibited IKKβ expression and suppressed NF-κB activity and its downstream target genes, including COX-2, cMYC, cyclin D1, MMP-2, MMP-9, CD24, CD44 and increased p21CIP1 and p27KIP1 that are known to be involved in proliferation, cell-cycle progression, metastasis and cancer stem cell marker protein. Breast cancer cells xenograft models indicate that treatment with GR agonists significantly reduced tumor growth, weight and volume. Overall, our data strongly suggest that GR agonists induced miR-708 and downstream suppression of NF-κB signaling which may be applicable as a novel therapeutic intervention in breast cancer treatment.
PMID: 30726934 [PubMed - as supplied by publisher]
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