Abstract
miR-374a has been reported to function as an oncogene during tumor pathogenesis. In this study, miR-374a is observed to reduce nasopharyngeal carcinoma (NPC) cell proliferation, migration, invasion, metastasis and cisplatin (DDP) resistance in vitro and in vivo. Mechanistic analyses indicate that miR-374a directly targets CCND1 to inactivate pPI3K/pAKT/c-JUN forming a negative feedback loop, as well as suppressing downstream signals related to cell cycle progression and epithelial-mesenchymal transition (EMT). Interestingly, we also observed that miR-374a direct targeting of CCND1 is modulated by tumor suppressor PDCD4 via suppressing pPI3K/pAKT/c-JUN signaling. In clinical specimens, miR-374a was positively and negatively correlated with expression of PDCD4 and CCND1, respectively. Our studies are the first to demonstrate that the miR-374a-CCND1-pPI3K/AKT-c-JUN feedback loop induced by PDCD4 supresses NPC cell growth, metastasis and chemotherapy resistance.
MeSH terms
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Animals
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Apoptosis Regulatory Proteins / genetics*
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Carcinoma / drug therapy
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Carcinoma / genetics*
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Carcinoma / metabolism
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Cell Cycle / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cisplatin / administration & dosage*
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Cisplatin / pharmacology
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Cyclin D1 / genetics*
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Drug Resistance, Neoplasm*
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Epithelial-Mesenchymal Transition / drug effects
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Feedback, Physiological
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Mice
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MicroRNAs / genetics*
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Nasopharyngeal Carcinoma
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Nasopharyngeal Neoplasms / drug therapy
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Nasopharyngeal Neoplasms / genetics*
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Nasopharyngeal Neoplasms / metabolism
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Neoplasm Metastasis
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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RNA-Binding Proteins / genetics*
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Signal Transduction / drug effects
Substances
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Apoptosis Regulatory Proteins
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CCND1 protein, human
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MIRN374 microRNA 374, human
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MicroRNAs
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PDCD4 protein, human
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RNA-Binding Proteins
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Cyclin D1
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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Cisplatin