Mechanism of senescence-associated microRNA inhibiting cell growth and metastasis

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We identified that senescent associated miRNA, SA-miRNA, miR-22 is down-regulated in various cancer cell lines including MCF-7, MDA-MB-231 and SiHa cells, suggesting that miR-22 should play important roles for cancer progression. Transfection of miR-22 strongly induces cellular senescence accompanied by enlarged morphology, senescent-associated b-Gal activity (SA-b-Gal) and senescent associated heterochromatin foci (SAHF) formation. By using 3-UTR luciferase assay and Western analysis, we identified CDK6, SP-1, SIRT1 and Histone H3.3 are targets of miR-22. Furthermore, synthetic miR-22 delivery significantly suppresses tumor growth and metastasis in vivo in a murine breast metastasis cancer model using MDA-MB-231 Luc cell lines. Our study provides the first evidence that the senescence-associated miRNA induces cellular senescence in human fibroblasts and cancer cells, and acts as tumor suppressor to play an important role in tumorigenesis.