Low expression of miR-7-5p promotes resistance to radiotherapy in lung cancer through direct upregulation of PKP2 expression

Lung cancer remains a significant global health challenge, with advanced stages often limiting surgical options and necessitating systemic therapies, such as radiotherapy. Resistance to radiotherapy frequently undermines the treatment efficacy. This study explored the role of miR-7-5p in modulating the expression and radiosensitivity of plakophilin-2 (PKP2) in non-small cell lung cancer (NSCLC). Using clonogenic assays, CCK-8 assays, immunofluorescence staining, western blotting, and reporter gene assays, we assessed the effects of miR-7-5p overexpression and inhibition on A549 NSCLC cells. The results show that miR-7-5p overexpression enhanced radiosensitivity by increasing DNA damage (evidenced by higher γ-H2AX foci) and inhibiting non-homologous end joining (NHEJ) repair. Bioinformatic and experimental validation identified PKP2 as a direct target of miR-7-5p. PKP2 overexpression mitigated the radiosensitizing effects of miR-7-5p, confirming the miR-7-5p/PKP2 axis's role in regulating radiosensitivity. This study highlights the potential of targeting the miR-7-5p/PKP2 pathway to overcome radiotherapy resistance in NSCLC and offers a promising therapeutic approach to enhance treatment outcomes.