Upregulation of miR-760 and miR-186 Is Associated with Replicative Senescence in Human Lung Fibroblast Cells

We have previously shown that microRNAs (miRNAs) miR-760, miR-186, miR-337-3p, and miR-216b stimulate premature senescence through protein kinase CK2 (CK2) downregulation in human colon cancer cells. Here, we examined whether these four miRNAs are involved in the replicative senescence of human lung fibroblast IMR-90 cells. miR-760 and miR-186 were significantly upregulated in replicatively senescent IMR-90 cells, and their joint action with both miR-337-3p and miR-216b was necessary for efficient downregulation of the alpha subunit of CK2 (CK2 alpha) in IMR-90 cells. A mutation in any of the four miRNA-binding sequences within the CK2 alpha 3'-untranslated region (UTR) indicated that all four miRNAs should simultaneously bind to the target sites for CK2 alpha downregulation. The four miRNAs increased senescence-associated. beta-galactosidase (SA-beta-gal) staining, p53 and p21(Cip1/WAF1) expression, and reactive oxygen species (ROS) production in proliferating IMR-90 cells. CK2 alpha overexpression almost abolished this event. Taken together, the present results suggest that the upregulation of miR-760 and miR-186 is associated with replicative senescence in human lung fibroblast cells, and their cooperative action with miR-337-3p and miR-216b may induce replicative senescence through CK2 alpha downregulation-dependent ROS generation.