Role of microRNAs in cellular senescence

Senescence is recognized as a permanent arrest of cell proliferation triggered by telomere shortening or various stresses. Senescence imposes a barrier to tumorigenesis and contributes to aging. It represents a cell response that encompasses gene expression regulation at transcriptional and post-transcriptional levels. MicroRNAs (miRNAs or miRs) are small non-coding RNAs that regulate diverse biological processes through their control of mRNA degradation or translation. In this work, we have analyzed the expression profiles of 284 known microRNAs in senescent relative to early-passage IMR90 human diploid fibroblasts. We found that 179 miRNAs were expressed at significant level and that in senescent cells 47% were downregulated (at least 2-fold) and 19% were upregulated at same extent. With only few exceptions, a similar expression profile was observed in human senescent BJ fibroblasts, as well as in young IMR90 fibroblasts treated with a mild chronic oxidative stress or with etoposide. The upregulated miRNAs, validated by Quantitative Real Time PCR, included miR-23b, miR-30e-5p, miR-126*, miR-134, miR-200c, miR-210, miR-376a*, miR-369-5p, miR-379, miR-410, miR-432, miR-485-5p, miR-486, miR-494, miR-542-5p, miR-654, miR-656 and some of them (miR-134, miR-369-3p, miR-376a*, miR-379, miR-410, miR-432, miR-485-5p, miR-494, miR-654 and miR-656) are members of an imprinted region of human chromosome 14. We found that ectopic expression of some of the upregulated microRNAs (miR-210, miR-376a*, miR-486, miR-494, miR-542-5p, miR-654) in young proliferating IMR90 fibroblasts triggers a premature senescent phenotype showing typical markers of senescence and accompanied also by the appearance of molecular complexes involved in different patterns of DDR (DNA damage response).