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Abstract
BackgroundMalignant 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.MethodsPotentially 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.ResultsThe 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 β-Catenin. In addition, we found alleviated radioresistance upon miR-34c overexpression or β-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.ConclusionmiR-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.
Highlights
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
Results miR‐34c is downregulated in NPC tissues and cell lines and negatively associated with radioresistance To find the key inhibiting miRNAs for NPC initiation, progression and radioresistance, we conducted miRNA sequencing for NP69, CNE-2 and CNE-2R cells (Fig. 1a)
We found that miR-34c significantly decreased in NPC tissue samples compared to normal nasopharynx samples (Fig. 1c, d), and expressed even lower in radioresistance NPC tissue samples compared to their radiosensitive counterparts (Fig. 1e), which in accordance with the miRNA sequencing results for cell lines (Fig. 1b)
Summary
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. 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. Nasopharyngeal carcinoma (NPC) is a common malignant tumor in Southeast Asia, including southern area of China such as Guangdong and Guangxi province [1]. Some patients with early-stage NPC can be cured by RT, but due to malignant behavior and resistance to radiotherapy, 19% to 29% of patients still suffer local recurrence or distant metastasis after RT [2, 3]. Our previous studies found that radioresistant NPC cells showed higher EMT level compared to normal NPC cells [8]
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