MicroRNA miR-885-5p targets CDK2 and MCM5, activates p53 and inhibits proliferation and survival

Abstract

Several microRNA (miRNA) loci are found within genomic regions frequently deleted in primary neuroblastoma, including miR-885-5p at 3p25.3. In this study, we demonstrate that miR-885-5p is downregulated on loss of 3p25.3 region in neuroblastoma. Experimentally enforced miR-885-5p expression in neuroblastoma cell lines inhibits proliferation triggering cell cycle arrest, senescence and/or apoptosis. miR-885-5p leads to the accumulation of p53 protein and activates the p53 pathway, resulting in upregulation of p53 targets. Enforced miR-885-5p expression consistently leads to downregulation of cyclin-dependent kinase (CDK2) and mini-chromosome maintenance protein (MCM5). Both genes are targeted by miR-885-5p via predicted binding sites within the 3 0 -untranslated regions (UTRs) of CDK2 and MCM5. Transcript profiling after miR-885-5p introduction in neuroblastoma cells reveals alterations in expression of multiple genes, including several p53 target genes and a number of factors involved in p53 pathway activity. Taken together, these data provide evidence that miR-885-5p has a tumor suppressive role in neuroblastoma interfering with cell cycle progression and cell survival. Cell Death and Differentiation (2011) 18, 974-984; doi:10.1038/cdd.2010.164; published online 14 January 2011MicroRNAs (miRNAs) are non-coding short (18-24 nt) RNAs, controlling gene expression post trancriptionally, via inhibiting translation or triggering degradation of multiple target mRNAs. They are vitally important regulators of proliferation, differentiation and apoptosis. Upregulated and downregulated miRNAs have been found in different malignancies, implicating miRNAs as oncogenes or tumor suppressors. 1 The increasing body of evidence for miRNA involvement in tumorigenesis has prompted the search in cancer-associated genomic regions for miRNA loci. 2 In a deletion region at 13q14, miR-15 and miR-16, are downregulated in B-cell chronic lymphocytic leukemia. Both miR-15 and miR-16 negatively regulate BCL2 and positively regulate apoptosis, which could explain their frequent inactivation in leukemia. 3 Later, miR-34a at 1p36 emerged as a tumor suppressor gene (TSG). Several independent studies demonstrated anti-proliferative and pro-apoptotic potential of miR-34a. 4,5 The potential for involvement of as yet unreported miRNAs in cancer pathogenesis is great.Neural crest-derived neuroblastoma, one of the most common solid tumors in children, is frequently characterized as an 'enigmatic neoplasm'. Neuroblastoma has the highest rate of spontaneous regression of all human malignancies, however, B40% of neuroblastomas rapidly progress despite multimodal treatment regimes. 6,7 TP53 mutations are rare in neuroblastoma, which very often retain functional p53, suggesting that inhibitors of the p53 pathway or loss of p53 pathway positive regulators may be involved in neutralizing p53 activity. 8,9 Neuroblastomas with poor outcome are subdivided into at least two biologically distinct groups, either with or without amplification of the MYCN oncogene....

MicroRNA therapy inhibits hepatoblastoma growth in vivo by targeting β‐catenin and Wnt signaling

“…Interestingly, miR‐1205 and let‐7i are positively regulated by p53,29, 30 and miR‐885‐5p and miR‐449b activate the p53 pathway 31, 32. Therefore, our results further strengthen the idea that the regulation of beta‐catenin by miRNAs is linked to p53 signaling 17.…”

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