Epigenetic Silencing of the Myelopoiesis Regulator microRNA-223 by the AML1/ETO Oncoprotein

Fazi, Francesco; Racanicchi, Serena; Zardo, Giuseppe; Starnes, Linda M.; Mancini, Marco; Travaglini, Lorena; Diverio, Daniela; Ammatuna, Emanuele; Cimino, Giuseppe; Lo‐Coco, Francesco; Grignani, Francesco; Nervi, Clara

doi:10.1016/j.ccr.2007.09.020

Cited by 369 publications

(335 citation statements)

References 39 publications

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“…MiR-223 is deregulated in acute myeloid leukemia (14,15). We find that miR-223 is also expressed in the nervous system and we demonstrate that miR-223 controls the expression and function of GluR2 and NR2B subunits of the glutamate receptor.…”

mentioning

confidence: 75%

MicroRNA-223 is neuroprotective by targeting glutamate receptors

Harraz

Eacker²,

Wang³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

254

183

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Stroke is a major cause of mortality and morbidity worldwide. Extracellular glutamate accumulation leading to overstimulation of the ionotropic glutamate receptors mediates neuronal injury in stroke and in neurodegenerative disorders. Here we show that miR-223 controls the response to neuronal injury by regulating the functional expression of the glutamate receptor subunits GluR2 and NR2B in brain. Overexpression of miR-223 lowers the levels of GluR2 and NR2B by targeting 3′-UTR target sites (TSs) in GluR2 and NR2B, inhibits NMDA-induced calcium influx in hippocampal neurons, and protects the brain from neuronal cell death following transient global ischemia and excitotoxic injury. MiR-223 deficiency results in higher levels of NR2B and GluR2, enhanced NMDA-induced calcium influx, and increased miniature excitatory postsynaptic currents in hippocampal neurons. In addition, the absence of MiR-223 leads to contextual, but not cued memory deficits and increased neuronal cell death following transient global ischemia and excitotoxicity. These data identify miR-223 as a major regulator of the expression of GluR2 and NR2B, and suggest a therapeutic role for miR-223 in stroke and other excitotoxic neuronal disorders.

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mentioning

confidence: 75%

MicroRNA-223 is neuroprotective by targeting glutamate receptors

Harraz

Eacker²,

Wang³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

254

183

View full text Add to dashboard Cite

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“…It has been reported that CpG islands within introns can act as promoters that are regulated by DNA methylation (Lyle et al, 2000). Along a 340-bp sequence (nucleotides À203 to 137) containing miR-223, DNA methylation of six CpG dinucleotides has been reported to contribute to miRNA repression (Fazi et al, 2007). Notably, miR520e is located at chromosome 19q13.42, locus spans a large, poorly characterized miRNA cluster (Li et al, 2009a).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-520e suppresses growth of hepatoma cells by targeting the NF-κB-inducing kinase (NIK)

et al. 2011

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MicroRNAs (miRNAs) are small, non-coding RNAs that can act as oncogenes or tumor suppressor genes in human cancer. Emerging evidence indicates that deregulation of miRNAs contributes to the hepatocarcinogenesis. In the present study, we demonstrated that the levels of miR-520e were dramatically decreased in examined hepatoma cell lines and clinical hepatocellular carcinoma (HCC) tissues. Moreover, we found that DNA hypermethylation in the upstream region of miR-520e resulted in the downregulation of miR-520e. Next, we demonstrated that introduction of miR-520e dramatically suppressed the growth of hepatoma cells in vitro and in vivo, whereas silencing the expression of miR-520e by anti-miR-520e resulted in a promoted cell proliferation, suggesting that miR-520e may be a novel tumor suppressor. Further studies revealed that NF-jB-inducing kinase (NIK) was one of the direct target genes of miR-520e, as miR-520e directly bound to the 3 0 untranslated region of NIK, which reduced the expression of NIK at the levels of mRNA and protein. Moreover, silencing of NIK was able to inhibit the growth of hepatoma cells, similar to the effect of miR-520e overexpression on growth of hepatoma cells. Meanwhile, the knockdown of NIK expression reversed the enhanced proliferation mediated by anti-miR-520e. In addition, miR-520e significantly decreased the phosphorylation of ERK1/2 (p-ERK1/2) and depressed the transcriptional activity and nuclear translocation of nuclear factor jB (NF-jB) (p65). These results suggest that miR-520e suppresses the growth of hepatoma cells by targeting NIK involving the NIK/p-ERK1/2/NF-jB signaling pathway. Finally, we showed that the intratumoral injection with miR-520e was able to directly repress the growth of hepatoma cells in the nude mice. Thus, our finding provides new insight into the mechanism of hepatocarcinogenesis, indicating a therapeutic potential of miR-520e in the treatment of HCC.

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“…More recently, changes in the methylation pattern of DNA regions coding for micro-RNAs (miRs) that modulate the expression of oncogenes or tumor suppressors have been reported (Datta et al, 2008;Huang et al, 2009;Pallasch et al, 2009). Inversely, it has been observed that oncofusion proteins can epigenetically silence miRs that are critically involved in lineage specification (Fazi et al, 2007). Altogether, these studies argue that locally altered methyl-CpG densities can result in the deregulation of multiple regulatory pathways, which are relevant for tumorigenesis.…”

Section: Current Therapeutic Paradigms To Treat Cancermentioning

confidence: 99%

Towards novel paradigms for cancer therapy

et al. 2010

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Cancer is a complex progressive multistep disorder that results from the accumulation of genetic and epigenetic abnormalities, which lead to the transformation of normal cells into malignant derivatives. Despite enormous progress in the understanding of cancer biology including the decryption of multiple regulatory networks governing cell growth and death, and despite the possibility of analyzing (epi)genetic deregulation at the genome-wide scale, cancertargeted therapy is still the exception. In fact, to date there are still far too few examples of therapies leading to cure; treatment-derived toxicity is a major issue, and cancer remains to be one of the largest causes of death worldwide. The purpose of this review is to discuss the state of the art of cancer therapy with respect to the key issue of any treatment, namely its target selectivity. Therefore, we recapitulate and discuss current concepts and therapies targeting tumorspecific features, including oncofusion proteins, aberrant kinase activities and epigenetic tumor makeup. We analyze strategies designed to induce tumor-selective death such as the use of oncolytic virus, tumoricidal proteins (NS1, Eorf4, apoptin, HAMLET (human a-lactalbumin made lethal to tumor cells)) and activation of signaling pathways involved in tumor surveillance. We emphasize the potential of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway, an essential component of the evolutionary developed defense systems that eradicate malignant cells. Finally, we discuss the necessity of targeting tumor-initiating cells (TICs) to avoid relapse and increase the chances of complete remission, and describe emerging concepts that might provide novel avenues for cancer therapy.

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Epigenetic Silencing of the Myelopoiesis Regulator microRNA-223 by the AML1/ETO Oncoprotein

Cited by 369 publications

References 39 publications

MicroRNA-223 is neuroprotective by targeting glutamate receptors

MicroRNA-223 is neuroprotective by targeting glutamate receptors

MicroRNA-520e suppresses growth of hepatoma cells by targeting the NF-κB-inducing kinase (NIK)

Towards novel paradigms for cancer therapy

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