Down-regulation of miR-373 increases the radiosensitivity of lung cancer cells by targeting TIMP2.

BACKGROUND: Radiotherapy is a widely used effective treatment for lung cancer in clinic. MicroRNAs (miRNAs) have been proved to play an important role in radiation response. This study aimed to explore the regulatory role and mechanism of miR-373 in lung cancer cell radiosensitivity.

METHODS: qRT-PCR was used to analyze the expression of miR-373 in lung cancer tissues and cell lines. MiR-373 expression was overexpressed or knocked down by transfection with miR-373 mimic or inhibitor. The effects of miR-373 on cell radiosensitivity, migration and invasion were evaluated by clonogenic assay, migration and invasion assay, respectively. Luciferase reporter assay was used to verify whether TIMP2 was a target gene of miR-373. Expression of TIMP2 and signaling pathway molecules were analyzed by western blot.

RESULTS: MiR-373 was upregulated in lung cancer tissues and cell lines. Overexpression of miR-373 resulted in decreased radiosensitivity and increased migration and invasion of lung cancer cells, whereas miR-373 downregulation got opposite results. Luciferase reporter assay confirmed that TIMP2 was a target gene of miR-373. Knockdown of TIMP2 reversed the effects on radiosensitivity, migration and invasion in miR-373 inhibitor-transfected cells. Mechanistically, we found that miR-373 downregulation inhibited PI3K/AKT and Smad signaling pathways by targeting TIMP2.

CONCLUSIONS: Downregulation of miR-373 increased radiosensitivity and inhibited migration and invasion of lung cancer cells through targeting TIMP2 and thus regulating PI3K/AKT and Smad pathways. MiR-373 might be a potential therapeutic target for the treatment of lung cancer.