Abstract
MicroRNAs regulate gene expression by repressing translation or directing sequence-specific degradation of their complementary mRNA. We recently reported that miR-203 is down-regulated, and its exogenous expression inhibits cell growth in canine oral malignant melanoma tissue specimens as well as in canine and human malignant melanoma cells. A microRNA target database predicted E2F3 and ZBP-89 as putative targets of microRNA-203 (miR-203). The expression levels of E2F3a, E2F3b, and ZBP-89 were markedly up-regulated in human malignant melanoma Mewo cells compared with those in human epidermal melanocytes. miR-203 significantly suppressed the luciferase activity of reporter plasmids containing the 3'-UTR sequence of either E2F3 or ZBP-89 complementary to miR-203. The ectopic expression of miR-203 in melanoma cells reduced the levels of E2F3a, E2F3b, and ZBP-89 protein expression. At the same time, miR-203 induced cell cycle arrest and senescence phenotypes, such as elevated expression of hypophosphorylated retinoblastoma and other markers for senescence. Silencing of E2F3, but not of ZBP-89, inhibited cell growth and induced cell cycle arrest and senescence. These results demonstrate a novel role for miR-203 as a tumor suppressor acting by inducing senescence in melanoma cells.
Highlights
MicroRNA-203 is down-regulated, and its exogenous expression inhibits cell growth in human melanoma cells
This study demonstrated that the ectopic expression of miR203, which functions as anti-oncomir in human and canine malignant melanoma cells [25], induced cellular senescence by targeting E2F3 in human melanoma Mewo and A2058 cells
A previous study of ours showed that miR-205 as well as miR-203 is downregulated in human and canine malignant melanoma cells [25]
Summary
MicroRNA-203 is down-regulated, and its exogenous expression inhibits cell growth in human melanoma cells. Silencing of E2F3, but not of ZBP-89, inhibited cell growth and induced cell cycle arrest and senescence These results demonstrate a novel role for miR-203 as a tumor suppressor acting by inducing senescence in melanoma cells. It has been suggested that ZBP-89, a Krüppel-type zinc finger transcription factor that binds to GCrich sequences, induces senescence by inhibiting p16 expression in human lung cancer [20]. It was reported that miR-205 in human melanoma cells induces senescence by targeting E2F1 [21]. We reported that miR-203 and -205 are down-regulated in human and canine melanoma cells and that the ectopic expression of miR-203 and -205 inhibits their cell growth [25]. Our data suggest anti-oncogenic miR-203 to be a newly recognized senescence-associated miRNA
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