MicroRNAs/TP53 feedback circuitry in glioblastoma multiforme

Abstract

MicroRNAs (miRNAs) are increasingly implicated in regulating cancer initiation and progression. In this study, two miRNAs, miR-25 and -32, are identified as p53-repressed miRNAs by p53-dependent negative regulation of their transcriptional regulators, E2F1 and MYC. However, miR-25 and -32 result in p53 accumulation by directly targeting Mdm2 and TSC1, which are negative regulators of p53 and the mTOR (mammalian target of rapamycin) pathway, respectively, leading to inhibition of cellular proliferation through cell cycle arrest. Thus, there is a recurrent autoregulatory circuit involving expression of p53, E2F1, and MYC to regulate the expression of miR-25 and -32, which are miRNAs that, in turn, control p53 accumulation. Significantly, overexpression of transfected miR-25 and -32 in glioblastoma multiforme cells inhibited growth of the glioblastoma multiforme cells in mouse brain in vivo. The results define miR-25 and -32 as positive regulators of p53, underscoring their role in tumorigenesis in glioblastoma. G lioblastoma multiforme (GBM) is by far the most common and aggressive tumor of the CNS. Despite recent improvements in surgery, radiation therapy, and cytotoxic chemotherapy, the prognosis for GBM remains grim, with median survival time <1 y after diagnosis. Of all glial tumors, GBM seems to exhibit the greatest number of genetic changes (1). The TP53 tumor suppressor gene, a transcription factor for numerous genes involved in cell cycle control, DNA repair, apoptosis, and angiogenesis (2, 3), is one of the most frequently mutated genes in human cancer. Given its profound effects in either inhibiting cell proliferation or inducing apoptosis, the expression levels of the TP53 gene product, p53, are tightly controlled through a feedback loop involving the p53 downstream target gene, Mdm2, which negatively regulates p53 through Mdm2-mediated ubiquitination of p53 (4). As such, even modest changes in the Mdm2 level can perturb the p53 protein level and affect the tumorigenesis process.MicroRNAs (miRNAs), small noncoding RNAs of ∼22 nt that mediate posttranscriptional silencing of specific target mRNAs, are being increasingly recognized as an important determinant of tumor development and progression (5). Deregulated miRNAs were suggested to exert their function in cancer through silencing of key cell fate regulators by directly binding their 3′ UTR (6, 7). Furthermore, miRNAs cooperatively function with certain transcription factors (TFs) in the regulation of mutual sets of target genes, allowing the coordinated modulation of gene expression both transcriptionally and posttranscriptionally. Specifically, it has been revealed that there is a recurring network motif in which a TF regulates the miRNA with which it cooperates in regulating a common set of targets (8).Several studies have implicated p53 in the regulation of miRNAs expression (9-11). However, most miRNAs studied so far are positively correlated with p53 expression, whereas miRNAs repressed by this tumor suppressor have rarely been studied. Here, we...

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miRNAs link metabolic reprogramming to oncogenesis

“…MiR-25 and miR-32 induce accumulation of p53 and subsequently inhibition of glioblastoma cell growth [124]. MiR-7 has been found to target YY1, a p53 suppressor.…”

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“…[21][22][23][24][25][26] Another report indicated miR-23b promoters were responsive to p53. 27 Therefore, we explored whether miR-23b expression in DN is controlled by known transcription factors, such as p53.…”