Exosomes overexpressing miR-34c inhibit malignant behavior and reverse the radioresistance of nasopharyngeal carcinoma.

BACKGROUND: Malignant behavior and radioresistance, which severely limits the efficacy of radiation therapy (RT) in nasopharyngeal carcinoma (NPC), are associated with tumor progression and poor prognosis. Mesenchymal stem cells (MSCs) are used as a therapeutic tool in a variety of tumors. The aim of this study was to reveal the effect of tumor suppressor microRNA-34c-5p (miR-34c) on NPC development and radioresistance, as well as to confirm that exosomes derived from MSCs overexpressing miR-34c restore the sensitivity to radiotherapy in NPCs. METHODS: Potentially active microRNAs were screened by cell sequencing, Gene Expression Omnibus (GEO) database analysis, and analysis of clinical serum samples from 70 patients. The expression of genes and proteins was detected by Western blotting, quantitative reverse transcription PCR (qRT-PCR), and immunohistochemistry (IHC). Proliferation, apoptosis, invasion, migration and radioresistance of NPC were detected. Luciferase reporter assays were used to verify the interactions of microRNAs with their downstream targets. MSCs exosomes were isolated by ultrafiltration and verified by electron microscopy and nanoparticle tracking technology. RESULTS: The expression of miR-34c was associated with the occurrence and radiation resistance of NPC. In vitro and in vivo experiments indicated that overexpression of miR-34c inhibit malignant behavior such as invasion, migration, proliferation and epithelial-mesenchymal transition (EMT) in NPCs by targeting ß-Catenin. In addition, we found alleviated radioresistance upon miR-34c overexpression or ß-catenin knockdown in NPCs. Exosomes derived from miR-34c-transfected MSCs attenuated NPC invasion, migration, proliferation and EMT. Moreover, miR-34c-overexpressing exosomes drastically increased radiation-induced apoptosis in NPC cells. CONCLUSION: miR-34c is a tumor suppressor miR in NPC, which inhibits malignant behavior as well as radioresistance of tumor. Therefore, exogenous delivery of miR-34c to NPCs via MSC exosomes inhibits tumor progression and increases the efficiency of RT. Combination IR with miR-34c-overexpressing exosomes may be effective treatment for radioresistant NPCs.

The Double-Edge Role of the Addition of Adjuvant Chemotherapy to Concurrent Chemoradiotherapy in the Treatment of Nasopharyngeal Carcinoma.

PURPOSE: To construct a prognostic index (PI) for overall survival (OS) to stratify nasopharyngeal carcinoma (NPC) into high-risk and low-risk groups. We also applied the model to investigate the role of the addition of adjuvant chemotherapy (AC) to concurrent chemoradiotherapy (CCRT) regimens for the treatment of NPC. METHODS: A prognostic model was established based on a retrospective study of 362 patients from January 2008 to June 2011. The discriminative and calibration abilities of the model were evaluated by Harrell's concordance index (C-index), and calibration curves. Bootstrapping was used to perform for internal validation. External validation was conducted using 324 patients diagnosed with NPC from July 2011 to December 2012 at the same institution. Survival analyses were performed between CCRT-AC and CCRT alone groups for the high-risk and low-risk groups. RESULTS: The primary PI comprised covariates that were associated with OS in the training cohort, including T stage, N stage, age, and plasma alkaline phosphatase (ALP). Internal and external validation showed that the discrimination of the PI for OS was significantly better than that of the 8th edition AJCC staging system. Discretization by using a fixed PI score cut-off of 407.96 determined from the training data set yielded high- and low-risk subgroups with distinct OS outcomes in the validation cohort. Adjuvant chemotherapy improved OS in high-risk patients (HR 0.620, 95% CI 0.408 to 0.941; P = 0.023) but increased the risk of distant metastasis (HR, 4.222, 95% CI, 0.959 to 18.585; P = 0.038) in low-risk patients. CONCLUSION: The proposed prognostic model achieved good prediction and calibration of OS for patients with NPC. The addition of adjuvant chemotherapy might be a double-edged sword, bringing survival benefit to high-risk patients but greater risk of distant metastasis to low-risk patients.