Affiliations: Department of Radiation Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning 110042, China
Correspondence:
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Corresponding author: Na Zhang, Department of Radiation Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Dadong District, Shenyang, Liao- ning 110042, China. Tel.: +86 189 0091 7253; E-mail: zhangna@cancerhosp-ln-cmu.com.
Abstract: BACKGROUND: Micro(mi)RNAs are a series of 20–24 nt non-coding small-molecule single-stranded RNAs that are believed to be closely related to tumor occurrence, development and other biological processes. MicroRNA-125a modulates radiochemotherapy sensitivity. However, the mechanism by which miRNA-125a regulates radiation resistance by lung cancer cells is yet to be elucidated. OBJECTIVE: The present study was designed to explore the biological role of miR-125a in regulating radioresistance in non-small cell lung carcinoma (NSCLC). METHODS AND RESULTS: The expression of miR-125a was assessed by quantitative real-time PCR in the human lung cancer cell lines, A549 and LTEP-a2. Notably, we found that miRNA-125a-5p regulated lung cancer radiosensitivity. We found that miRNA-125a-5p was more highly expressed in LTEP-a2 cells, which showed radiosensitivity compared to A549 cells with lower expression of miRNA-125a-5p. In addition, we up-regulated or down-regulated miR-125a-5p expression using an miR-125a-5p mimic or inhibitor, respectively, to reverse radioresistance. Flow cytometry revealed that the mimic increased the apoptotic rate as well as the expression of the apoptosis-related protein, cleaved poly ADP-ribose polymerase (PARP). Gene detection by luciferase reporter showed that sirtuin (SIRT)7 is a direct target of miR-125a-5p. Inhibiting SIRT7 using a small interfering RNA (siSIRT) abrogated resistance to radiation. In addition, the overexpression of SIRT7 decreased radiation-induced cell apoptosis. CONCLUSION: Our results indicated that the miR-125a level varies in NSCLC cell lines with different radiosensitivities. We demonstrated that miR-125a-5p upregulated SIRT7 and further upregulated apoptosis in lung cancer cells to increase their radiosensitivity. Our findings provide new directions for improving radiosensitivity in malignant lung tumors.
