MiR-382-3p downregulation contributes to the carcinogenesis of lung adenocarcinoma by promoting AKT SUMOylation and phosphorylation.

Abstract

Lung adenocarcinoma (LA), the primary histological type of non-small cell lung cancer, is still incurable; its diagnosis and treatment remain a major clinical challenge. A previous study by our group examined the microRNA (miRNA/miR) expression profile in the extracellular vesicles from patients with LA and healthy controls and indicated that miR-382-3p levels were reduced in patients with LA. However, the precise roles of miR-382-3p in LA have so far remained elusive. In the present study, the miR-382-3p levels in tumor and adjacent non-tumor control samples from 78 patients with LA were examined and it was identified that miR-382-3p expression was reduced in LA tumor samples compared with that in adjacent non-tumor control tissues (P=0.022). Furthermore, miR-382-3p overexpression inhibited LA growth in a xenograft mouse model. Prediction results indicated that miR-382-3p may regulate protein ubiquitination and SUMOylation. Small ubiquitin-like modifier (SUMO)1 activating enzyme subunit 1 (SAE1), one of the key components of the SUMO-activating complex, was identified as a direct target of miR-382-3p via dual-luciferase and immunoblotting assays. In patients with LA, miR-382-3p expression was negatively correlated with SAE1 protein levels (r=-0.39, P<0.05) and higher SAE1 expression contributed to poor prognosis (P<0.01). Using immunoprecipitation, it was identified that miR-382-3p reduction-induced SAE1 overexpression upregulated AKT SUMOylation, which further promoted AKT phosphorylation and activated the AKT signaling pathway. miR-382-3p inhibition promoted proliferation and inhibited apoptosis in LA cell lines, which was restored by SAE1 knockdown. In conclusion, the present study revealed that downregulation of miR-382-3p contributed to the carcinogenesis of LA via upregulation of SAE1 and promotion of AKT SUMOylation, providing a candidate target for LA treatment.