RESUMO
Radiotherapy is a common method for the treatment of lung adenocarcinoma, but it often fails due to the relative non-susceptibility of lung adenocarcinoma cells to radiation. We aimed to discuss the related mechanisms by which miR-126-5p might mediate radiosensitivity of lung adenocarcinoma cells. The binding affinity between miR-126-5p and EZH2 and between KLF2 and BIRC5 was identified using multiple assays. A549 and H1650 cells treated with X-ray were transfected with miR-126-5p mimic/inhibitor, oe-EZH2, or si-KLF2 to detect cell biological functions and radiosensitivity. Finally, lung adenocarcinoma nude mouse models were established. miR-126-5p and KLF2 were poorly expressed, while EZH2 and BIRC5 were upregulated in lung adenocarcinoma tissues and cells. miR-126-5p targeted EZH2 to promote the KLF2 expression so as to inhibit BIRC5 activation. Both in vitro and in vivo experiments verified that elevated miR-126-5p inhibited cell migration and promoted apoptosis to enhance the sensitivity of lung adenocarcinoma cells to radiotherapy via the EZH2/KLF2/BIRC5 axis. Collectively, miR-126-5p downregulated EZH2 to facilitate the sensitivity of lung adenocarcinoma cells to radiotherapy via KLF2/BIRC5.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , MicroRNAs , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/radioterapia , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/radioterapia , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Tolerância a Radiação/genéticaRESUMO
BACKGROUND: Radiotherapy is the mainstay treatment for lung adenocarcinoma, yet remains highly susceptible to resistance. Fe3O4 magnetic nanoparticles (MNPs) possess the ability to induce biological therapeutic effects. Herein, the current study set out to explore the effects of Fe3O4 MNPs on radiosensitivity of lung adenocarcinoma cells. METHODS: Fe3O4 MNPs loaded with both negatively-charged small interfering RNA against baculoviral IAP repeat containing 5 (siBIRC5) and oligodeoxynucleotide antisense (AS-ODN) to generate co-delivery NPs, followed by evaluation. Gel retardation assay was further performed to determine the binding ability of Fe3O4 MNPs to AS-ODN/siBIRC5. The radiosensitizing effect of NPs on lung adenocarcinoma cells was determined in the absence or the presence of NPs or radiotherapy. A549 and H460 tumor-bearing mice were established, where tumor tissues were subjected to immunohistochemistry. RESULTS: NPs were successfully prepared and characterized. BIRC5 expression levels were augmented in tissues of lung cancer patients. Fe3O4 MNPs enhanced the uptake of siBIRC5 and AS-ODN by lung adenocarcinoma cells. The presence of NPs under magnetic field reduced the BIRC5 expression and elevated the DR5 expression in lung adenocarcinoma cells. Lung adenocarcinoma cells treated with NPs exhibited inhibited tumor cell migration and increased DNA damage. After magnetic field treatment, tumors were better suppressed in the tumor-bearing mice treated with NPs, followed by radiotherapy. CONCLUSION: Findings obtained in our study indicated that Fe3O4 MNPs-targeted delivery of siBIRC5 and AS-ODN enhances radiosensitivity, providing an innovative solution for the current clinically existing lung adenocarcinoma patients with radiotherapy resistance with a low risk of toxicity.
