Lung cancer is one of the leading causes of cancer-associated mortality. Non-small cell lung carcinoma (NSCLC) accounts for 70-85% of the total cases of lung cancer. Radioresistance frequently develops in NSCLC in the middle and later stages of radiotherapy. We investigated the role of miR-219a-5p in radioresistance of NSCLC. miR-219a-5p expression in serum and lung tissue of lung cancer patients was lower than that in control. Compared with radiosensitive NSCLC patients, miR-219a-5p expression was decreased in serum and lung tissue in radioresistant patients. miR-219a-5p expression level was negatively associated with radioresistance in NSCLC cell lines. Upregulation of miR-219a-5p increased radiosensitivity in radioresistant NSCLC cells in vitro and in vivo. Downregulation of miR-219a-5p decreased radiosensitivity in radiosensitive A549 and H358 cells. miR-219a-5p could directly bind in the 3’UTR of CD164 and negatively regulated CD164 expression. CD164 expression was higher in radioresistant NSCLC tissues than radiosensitive tissues. Upregulation of CD164 significantly inhibited miR-219a-5p-induced regulation of radiosensitivity in radioresistant A549 and H358 cells. Downregulation of CD164 significantly inhibited the effect of anti-miR-219a-5p on radiosensitive A549 and H358 cells. miR-219a-5p or downregulation of CD164 could increase apoptosis and γ-H2A histone family member X (γ-H2AX) expression in radioresistant cells in vitro and in vivo. Upregulation of CD164 could inhibit the effect of miR-219a-5p on apoptosis and γ-H2AX expression. Our results indicated that miR-219a-5p could inhibit CD164, promote DNA damage and apoptosis and enhance irradiation-induced cytotoxicity. The data highlight miR-219a-5p/CD164 pathway in the regulation of radiosensitivity in NSCLC and provide novel targets for potential intervention.

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