407004

MIR22

MIRN22|hsa-mir-22|miR-22;microRNA 22;MIR22;microRNA 22

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17p13.3

miscRNA

Count: 1; Generif

Cellular senescence acts as a barrier to cancer progression, and microRNAs (miRNAs) are thought to be potential senescence regulators. However, whether senescence-associated miRNAs (SA-miRNAs) contribute to tumor suppression remains unknown. Here, we report that miR-22, a novel SA-miRNA, has an impact on tumorigenesis. miR-22 is up-regulated in human senescent fibroblasts and epithelial cells but down-regulated in various cancer cell lines. miR-22 overexpression induces growth suppression and acquisition of a senescent phenotype in human normal and cancer cells. miR-22 knockdown in presenescent fibroblasts decreased cell size, and cells became more compact. miR-22-induced senescence also decreases cell motility and inhibits cell invasion in vitro. Synthetic miR-22 delivery suppresses tumor growth and metastasis in vivo by inducing cellular senescence in a mouse model of breast carcinoma. We confirmed that CDK6, SIRT1, and Sp1, genes involved in the senescence program, are direct targets of miR-22. Our study provides the first evidence that miR-22 restores the cellular senescence program in cancer cells and acts as a tumor suppressor.

Oncogenic c-Myc has been described to modulate the expression of a subset of microRNAs (miRNAs), which include miR-22; however, the mechanism through which a miRNA controls c-Myc activity remains unclear. Here we report a novel anti-c-Myc function mediated by miR-22. Ectopically expressed miR-22 inhibited cell proliferation and anchorage-independent growth of human cancer cell lines. Microarray screening and western analyses revealed that miR-22 repressed the c-Myc-binding protein MYCBP, a positive regulator of c-Myc. Consistent with this, reporter assays showed that miR-22-mediated MYCBP gene suppression largely depends on the conserved miR-22 target site within the MYCBP 3'-untranslational region (3'UTR), implying that MYCBP mRNA is a direct miR-22 target. Depletion of MYCBP using small interfering RNA (siRNA) recapitulated the miR-22-induced anti-growth effect on tumor cells, whereas ectopically expressed MYCBP rescued cells from the growth suppression mediated by miR-22. Moreover, repression of MYCBP by miR-22 downregulated a panel of E-box-containing c-Myc target genes. Our results suggest that miR-22 acts as a tumor suppressor through direct repression of MYCBP expression and subsequent reduction of oncogenic c-Myc activities. As c-Myc inhibits the expression of miR-22, we propose a novel positive feedback loop formed by oncogenic c-Myc to accelerate cell proliferation by suppressing miR-22, a potent inhibitor of MYCBP.