The Molecular Pathogenesis of Tumor-Suppressive miR-486-5p and miR-486-3p Target Genes: GINS4 Facilitates Aggressiveness in Lung Adenocarcinoma.

The involvement of passenger strands of miRNAs in the molecular pathogenesis of human cancers is a recent concept in miRNA research, and it will broaden our understanding of the molecular mechanisms of miRNA-mediated cancer. The analysis of our miRNA signature of LUAD revealed that both strands of pre- miR-486 ( miR-486-5p and miR-486-3p ) were downregulated in LUAD tissues. Ectopic expression of both miRNAs induced cell cycle arrest in LUAD cells, suggesting both strands of miRNAs derived from pre- miR-486 were tumor suppressive. Our in silico analysis showed a total of 99 genes may be under the control of both miRNAs in LUAD cells. Importantly, among these targets, the high expression of seven genes ( MKI67 , GINS4 , RRM2 , HELLS , MELK , TIMELESS , and SAPCD2 ) predicted a poorer prognosis of LUAD patients ( p < 0.05). We focused on GINS4 , a DNA replication complex GINS protein that plays an essential role in the initiation of DNA replication. Our functional assays showed that GINS4 was directly controlled by both strands of pre- miR-486 , and its aberrant expression facilitated the aggressive behavior of LUAD cells. GINS4 is attractive as a therapeutic target for this disease. MiRNA analysis, including passenger strands, will further improve our understanding of the molecular pathogenesis of LUAD.