miR-374a-CCND1-pPI3K/AKT-c-JUN feedback loop modulated by PDCD4 suppresses cell growth, metastasis, and sensitizes nasopharyngeal carcinoma to cisplatin.
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.
Cancer Center, TCM-Integrated Hospital, Southern Medical University, Guangzhou, China.|Institute of Respiratory Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, PR, China.|Cancer Research Institute, Southern Medical University, Guangzhou, PR, China.
Y
Y
Zhen
Cancer Center, TCM-Integrated Hospital, Southern Medical University, Guangzhou, China.|Cancer Research Institute, Southern Medical University, Guangzhou, PR, China.
W
W
Fang
Cancer Research Institute, Southern Medical University, Guangzhou, PR, China.
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M
Zhao
Cancer Center, TCM-Integrated Hospital, Southern Medical University, Guangzhou, China.
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R
Luo
Cancer Research Institute, Southern Medical University, Guangzhou, PR, China.
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Y
Liu
Cancer Research Institute, Southern Medical University, Guangzhou, PR, China.
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Q
Fu
Cancer Research Institute, Southern Medical University, Guangzhou, PR, China.
Y
Y
Chen
Cancer Research Institute, Southern Medical University, Guangzhou, PR, China.
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C
Cheng
Department of Pathology, School of Basic Medicine, Guangzhou Medical University, Guangzhou, PR, China.
Y
Y
Zhang
Cancer Research Institute, Southern Medical University, Guangzhou, PR, China.|Department of Pathology, School of Basic Medicine, Guangzhou Medical University, Guangzhou, PR, China.
Z
Z
Liu
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage* / Q000494:pharmacology; D019938:Cyclin D1 / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects
D051017:Apoptosis Regulatory Proteins; C530104:CCND1 protein, human; C587995:MIRN374 microRNA 374, human; D035683:MicroRNAs; C114487:PDCD4 protein, human; D016601:RNA-Binding Proteins; D019938:Cyclin D1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin