miR-374a-CCND1-pPI3K/AKT-c-JUN feedback loop modulated by PDCD4 suppresses cell growth, metastasis, and sensitizes nasopharyngeal carcinoma to cisplatin

• Published in: Oncogene 2017-01, Vol.36 (2), p.275-285
• Main Authors: Zhen, Y, Fang, W, Zhao, M, Luo, R, Liu, Y, Fu, Q, Chen, Y, Cheng, C, Zhang, Y, Liu, Z
• Format: Article
• Language: English
• Subjects: 13/109; 13/31; 13/51; 14/35; 42/89; 45/61; 45/90; 59/5; 631/67/1059; 631/67/1536; 631/67/322; 631/67/581; 64; 64/60; 82/1; 82/80; 96/95; Animals; Apoptosis; Apoptosis Regulatory Proteins - genetics; Cancer metastasis; Carcinoma; Carcinoma - drug therapy; Carcinoma - genetics; Carcinoma - metabolism; Care and treatment; Cell Biology; Cell Cycle - drug effects; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Chemotherapy; Cisplatin - administration & dosage; Cisplatin - pharmacology; Cyclin D1 - genetics; Development and progression; Diagnosis; Drug resistance; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition - drug effects; Feedback, Physiological; Gene Expression Regulation, Neoplastic - drug effects; Head & neck cancer; Human Genetics; Humans; Internal Medicine; Medicine; Medicine & Public Health; Mice; MicroRNAs; MicroRNAs - genetics; Nasopharyngeal cancer; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms - drug therapy; Nasopharyngeal Neoplasms - genetics; Nasopharyngeal Neoplasms - metabolism; Neoplasm Metastasis; Oncology; original-article; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; RNA-Binding Proteins - genetics; Signal Transduction - drug effects; Tumorigenesis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2016.201

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.