Downregulation of microRNA-324-3p inhibits lung cancer by blocking the NCAM1-MAPK axis through ALX4.

Abstract

Lung cancer remains the principal cause of cancer-related death worldwide. As microRNAs (miRNAs) are critically involved in lung cancer, we investigated the potential role of miR-324-3p in lung cancer via the ALX4/NCAM1/MAPK axis. The expression of miR-324-3p and ALX4 was detected in clinical samples, and their interaction confirmed by miRNA-targeted luciferase reporter assay. The mechanisms involved in the miR-324-3p-ALX4 interaction in lung cancer cell biological processes were analyzed through gain- and loss-of function approaches. In addition, cultured lung cancer cells were treated with the p38MAPK pathway activator P79350 in order to explore the role of this pathway in the abovementioned axis. Further, a tumor xenograft model in nude mice was constructed to confirm the in vitro findings. miR-324-3p was highly expressed in lung cancer tissues and cells, and inhibited the expression of ALX4 in A549 cells. After confirming the targeted inhibition of ALX4 by miR-324-3p, we showed that this interaction upregulated the expression of NCAM1 and activated the MAPK pathway. The inhibition of miR-324-3p could suppress lung cancer cell invasion, migration, and autophagy, and retarded the growth of subcutaneous tumors in nude mice. Downregulation of ALX4 or NCAM1 overexpression reversed these favorable effects of decreased miR-324-3p. Our study demonstrated the promotive effect of miR-324-3p on the development and progression of lung cancer, thus suggesting a new target for treatment of this devastating disease.