The MiR-4306/IGF2R Axis Modulates the Lung Adenocarcinoma Response to Irradiation and

Background: Lung adenocarcinoma accounts for more than 50% of non-small cell lung cancers. Dysregulated microRNAs (miRNAs) and coding genes play a critical role in lung adenocarcinoma irradiation resistance and might be promising therapeutic targets. In the present study, we demonstrate the effect of the miR-4306/IGF2R axis on malignant behaviors of lung adenocarcinoma cells and the response to irradiation.

Methods: Quantitative realtime-PCR and Western blot assays were applied for miR-4306 and IGF2R expression in tumors and cells. A CCK-8 assay kit was used to detect cell viability. Colony formation assay was implied to detect cell proliferation. Transwell assay was used to detect cell invasion. A subcutaneous tumor model was performed in nude mice to detect tumor formation . Hematoxylin & eosin (H&E) staining were used to observe pathological status of tumor in nude mice. To validate the miR-4306 binding IGF2R 3'-UTR, a dual-luciferase reporter assay was performed.

Results: The expression level of miR-4306 was dramatically upregulated in lung adenocarcinoma samples and cells, and could be induced by irradiation in a dose-dependent manner. In lung adenocarcinoma cells, miR-4306 overexpression significantly promoted cell viability and invasive abilities and attenuated the inhibitory effect of irradiation on malignant cancer cell behaviors. In a subcutaneous tumor model in nude mice, miR-4306 overexpression promoted tumor growth and attenuated the suppressive effect of irradiation on tumor growth. miR-4306 directly inhibited the expression of IGF2R. In lung adenocarcinoma cells without irradiation, IGF2R overexpression was inhibited, while IGF2R knockdown promoted cell viability and invasive abilities. The effects of miR-4306 overexpression were partially attenuated by IGF2R overexpression. In lung adenocarcinoma cells, suppressive role of irradiation on cancer cell viability and invasive abilities were enhanced by IGF2R overexpression, but attenuated by IGF2R knockdown. The effects of miR-4306 overexpression on cancer cell viability and invasive abilities were also partially attenuated by IGF2R overexpression in lung adenocarcinoma cells with irradiation. In tissue samples, expression of miR-4306 and IGF2R were negatively correlated.

Conclusions: The miR-4306/IGF2R axis could significantly affect lung adenocarcinoma progression and response to radiotherapy, and further investigation of the clinical implications of this axis is strongly recommended.