miR-22 represses cancer progression by inducing cellular senescence

Xu, Dan; Takeshita, Fumitaka; Hino, Yumiko; Fukunaga, Saori; Kudo, Yasusei; Tamaki, Aya; Matsunaga, Junko; Takahashi, Ryou U.; Takata, Takashi; Shimamoto, Akira; Ochiya, Takahiro; Tahara, Hidetoshi

doi:10.1083/jcb.201010100

Cited by 267 publications

(214 citation statements)

References 65 publications

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“…MiR‐22 was initially defined as one of the senescence‐associated microRNAs that represses cancer progression by inducing cell senescence (Xu et al ., 2011). However, a subsequent analysis revealed that miR‐22 is most prominently upregulated during cardiovascular aging, targeting minecan (osteoglycin, OGN; Jazbutyte et al ., 2013).…”

Section: Discussionmentioning

confidence: 99%

Age‐associated downregulation of vasohibin‐1 in vascular endothelial cells

2016

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SummaryVasohibin‐1 (VASH1) is an angiogenesis‐inhibiting factor synthesized by endothelial cells (ECs) and it also functions to increase stress tolerance of ECs, which function is critical for the maintenance of vascular integrity. Here, we examined whether the expression of VASH1 would be affected by aging. We passaged human umbilical vein endothelial cells (HUVECs) and observed that VASH1 was downregulated in old HUVECs. This decrease in VASH1 expression with aging was confirmed in mice. To explore the mechanism of this downregulation, we compared the expression of microRNAs between old and young HUVECs by performing microarray analysis. Among the top 20 microRNAs that were expressed at a higher level in old HUVECs, the third highest microRNA, namely miR‐22‐3p, had its binding site on the 3′ UTR of VASH1 mRNA. Experiments with microRNA mimic and anti‐miR revealed that miR‐22‐3p was involved at least in part in the downregulation of VASH1 in ECs during replicative senescence. We then clarified the significance of this defective expression of VASH1 in the vasculature. When a cuff was placed around the femoral arteries of wild‐type mice and VASH1‐null mice, neointimal formation was augmented in the VASH1‐null mice accompanied by an increase in adventitial angiogenesis, macrophage accumulation in the adventitia, and medial/neointimal proliferating cells. These results indicate that in replicative senescence, the downregulation of VASH1 expression in ECs was caused, at least in part, by the alteration of microRNA expression. Such downregulation of VASH1 might be involved in the acceleration of age‐associated vascular diseases.

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Section: Discussionmentioning

confidence: 99%

Age‐associated downregulation of vasohibin‐1 in vascular endothelial cells

2016

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“…Xu et al indicated that miR-22 plays roles both in cell senescence and tumorigenesis (8): the expression of miR-22 is induced by cell senescence while it is reduced in various malignant tumor cells. The authors also indicated that overexpression of miR-22 suppresses the development of breast cancer in vivo.…”

Section: Discussionmentioning

confidence: 99%

The expression of miR-124 increases in aged skin to cause cell senescence and it decreases in squamous cell carcinoma

Harada

Jinnin

Wang

et al. 2016

BST

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“…However, our results clearly demonstrate that at least in CGNPs, miR-22 slows down the cell cycle progression but does not induce neuronal differentiation, indicating that the reported presence of miR-22 in various differentiating cell types does not necessarily imply a direct role of miR-22 in the differentiation process. Moreover, miR-22 has also been demonstrated to have a potent antiproliferative effect in differ-ent cancer cell lines (30) and to induce senescence in fibroblasts (32). Thus, given that compounds that promote differentiation or senescence exert their effects primarily on the cell cycle, miR-22 may reflect a common antiproliferative element working in different cellular processes whereby a slowdown in the cell cycle is required.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA 22 Regulates Cell Cycle Length in Cerebellar Granular Neuron Precursors

Berenguer

Herrera

Vuolo

et al. 2013

Molecular and Cellular Biology

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During cerebellum development, Sonic hedgehog (Shh)-induced proliferation of cerebellar granular neuronal precursors (CGNPs) is potently inhibited by bone morphogenetic proteins (BMPs). We have previously reported the upregulation of TIEG-1 and Mash1, two antimitotic factors that modulate MYCN transcription and N-Myc activity, in response to BMP2. To gain further insight into the BMP antimitotic mechanism, we used microRNA (miRNA) arrays to compare the miRNAs of CGNPs proliferating in response to Shh with those of CGNPs treated with Shh plus BMP2. The array analysis revealed that miRNA 11 (miR-22) levels significantly increased in cells treated with BMP2. Additionally, in P7 mouse cerebellum, miR-22 distribution mostly recapitulated the combination of BMP2 and BMP4 expression patterns. Accordingly, in CGNP cultures, miR-22 overexpression significantly reduced cell proliferation, whereas miR-22 suppression diminished BMP2 antiproliferative activity. In contrast to BMP2, miR-22 did not induce neural differentiation but instead significantly increased cell cycle length. Consistent with the central role played by N-myc on CGNP proliferation, Max was revealed as a direct target of miR-22, and miR-22 expression caused a significant reduction of Max protein levels and N-myc/Max-dependent promoter activity. Therefore, we conclude that, in addition to the previously described mechanisms, miR-22 plays a specific role on downstream BMPs through cerebellum growth.

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miR-22 represses cancer progression by inducing cellular senescence

Abstract: The microRNA miR-22 targets CDK6, SIRT1, and Sp1—genes involved in regulation of the senescence program—to suppress cell growth and proliferation.

Cited by 267 publications

References 65 publications

Age‐associated downregulation of vasohibin‐1 in vascular endothelial cells

Age‐associated downregulation of vasohibin‐1 in vascular endothelial cells

The expression of miR-124 increases in aged skin to cause cell senescence and it decreases in squamous cell carcinoma

MicroRNA 22 Regulates Cell Cycle Length in Cerebellar Granular Neuron Precursors

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