ABSTRACT
Recurrence or metastasis resulting from radioresistance are the main challenges for the treatment of nasopharyngeal carcinoma (NPC). A great deal of evidence supports the role of abnormal expression of miRNAs in radioresistance and malignancy. In some cancers, miR-483-5p is associated with inferior disease-specific survival. Therefore, we investigated the role of miR-483-5p in NPC radiosensitivity and the mechanism by which the miR-483-5p affects the radiosensitivity of NPC cells. In this study, we show that the overexpression of miR-483-5p decreases the radiosensitivity of NPC cells in vitro and in vivo. Mechanistically, miR-483-5p exerts these functions by decreasing radiation-induced apoptosis and DNA damage, and by increasing NPC cell colony formation, via targeting death-associated protein kinase 1 (DAPK1). Finally, our results confirm that the upregulation of miR-483-5p is correlated with advanced clinical stage and inferior overall survival of patients with NPC. These findings provide novel insights into our understanding of the molecular mechanisms underlying therapy failure in NPC. Modulation of miR-483-5p and DAPK1 levels may provide a new approach for increasing the radiosensitivity of these tumors.
Subject(s)
Death-Associated Protein Kinases/genetics , MicroRNAs/genetics , Nasopharyngeal Carcinoma/genetics , Nasopharyngeal Neoplasms/genetics , Radiation Tolerance/genetics , 3' Untranslated Regions/genetics , Animals , Apoptosis/drug effects , Apoptosis/genetics , Apoptosis/radiation effects , Cell Line, Tumor , Chemoradiotherapy/methods , Death-Associated Protein Kinases/metabolism , Female , Gene Expression Regulation, Neoplastic , Humans , Mice, Inbred BALB C , Mice, Nude , Nasopharyngeal Carcinoma/metabolism , Nasopharyngeal Carcinoma/therapy , Nasopharyngeal Neoplasms/metabolism , Nasopharyngeal Neoplasms/therapy , RNA Interference , Survival Analysis , Xenograft Model Antitumor Assays/methodsABSTRACT
Loss of hair cells occurs after radiotherapy, which is a major treatment modality for head and neck cancers. In the lateral line neuromasts of zebrafish, hair cells regenerate rapidly from supporting cells after damage from ototoxins. To investigate hair cell regeneration after radiation damage, zebrafish larvae were exposed to radiation, and hair cells were counted and cell proliferation was detected in neuromasts. After irradiation exposure, cell proliferation was inhibited in neuromasts and the number of supporting cells remained stable. There was a gradual loss of hair cells in lateral line neuromasts, which was not followed by regeneration. An activator of Wnt signaling (1-azakenpaullone) promoted robust regeneration of hair cells in irradiated neuromasts. By the quantitative real-time PCR and immunofluorescence, dkk2, an inhibitory Wnt ligand, was identified upregulated in irradiated neuromasts. Accelerating the death process of irradiated hair cells by treatment with neomycin also restored the regenerative capacity of neuromasts. However, a proportion of the new hair cells died within several days after forced regeneration and baseline activity of proliferation in supporting cells remained unimproved. In conclusion, these findings suggested that radiation suppressed hair cell regeneration in zebrafish lateral line neuromasts through inhibition of Wnt signaling in supporting cells possibly by secreting anti-proliferation factors like dkk2. Maintaining a healthy supporting cell pool is vital for regeneration of hair cells.
Subject(s)
Cell Proliferation/radiation effects , Hair Cells, Auditory/radiation effects , Lateral Line System/radiation effects , Radiation, Ionizing , Wnt Signaling Pathway/radiation effects , Animals , Hair Cells, Auditory/metabolism , Lateral Line System/cytology , Lateral Line System/metabolism , Regeneration/radiation effects , ZebrafishABSTRACT
BACKGROUND: The prognostic role of 18F-fluorodeoxyglucose positron emission tomography CT (18F-FDG PET/CT) parameters is still controversial in nasopharyngeal carcinoma patients. We sought to perform a systematic review and meta-analysis to explore the prognostic value of maximal standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) on event-free survival (EFS) and overall survival (OS) in nasopharyngeal carcinoma patients. RESULTS: Fifteen studies comprising 1,938 patients were included in this study. The combined hazard ratios (HRs) for EFS were 2.63 (95%CI 1.71-4.05) for SUVmax, 2.55 (95%CI 1.49-4.35) for MTV, and 3.32 (95%CI 1.23-8.95) for TLG. The pooled HRs for OS were 2.07 (95%CI 1.54-2.79) for SUVmax, 3.86 (95%CI 1.85-8.06) for MTV, and 2.60 (95%CI 1.55-4.34) for TLG. The prognostic role of SUVmax, MTV and TLG remained similar in the sub-group analyses. METHODS: A systematic literature search was performed to identify studies which associated 18F-FDG PET/CT to clinical survival outcomes of nasopharyngeal carcinoma patients. The summarized HRs for EFS and OS were estimated by using fixed- or random-effect models according to heterogeneity between trials. CONCLUSIONS: The present meta-analysis confirms that high values of SUVmax, MTV and TLG predicted a higher risk of adverse events or death in patients with nasopharyngeal carcinoma, despite clinically heterogeneous nasopharyngeal carcinoma patients and the various methods adopted between these studies.
