Loss of microRNA-143/145 disturbs cellular growth and apoptosis of human epithelial cancers by impairing the MDM2-p53 feedback loop

Oncogene (Impact Factor: 8.46). 02/2012; doi: 10.1038/onc.2012.28. [Epub ahead of print].


Dysregulated microRNAs (miRNAs) have an important role in many malignant tumors. However, elucidating the roles of miRNAs in cancer biology, especially in epithelial cancers, remains an ongoing process. In this study, we show that both miR-143 and miR-145, which belong to the same miRNA cluster, can negatively modulate expression of their target gene, MDM2. The miR-143 and miR-145 is posttranscriptionally activated by upregulated p53, thereby generating a short miRNAs-MDM2-p53 feedback loop. Re-expression of these miRNAs suppresses cellular growth and triggers the apoptosis of epithelial cancer, in vitro and in vivo, by enhancing p53 activity via MDM2 turnover. Moreover, the miRNA-dependent MDM2 turnover contributes to the equilibrium of repeated p53 pulses in response to DNA damage stress. These findings suggest that MDM2 dysregulation caused by downregulation of miR-143 and miR-145 contributes to epithelial cancer development and has a key role in regulating cellular proliferation and apoptosis. Re-expression of miR-143 and miR-145 may be a reasonable strategy for treatment of epithelial cancers.Oncogene advance online publication, 13 February 2012; doi:10.1038/onc.2012.28.

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Available from: Jianjun Zhang,
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    • "miR-143 and miR-145 induce apoptosis and suppress proliferation of epithelial cancer cells in a p53-dependent manner, both in vitro and in vivo (Zhang et al., 2013). Furthermore, under conditions where DNA damage elicits oscillations in p53 and Mdm2 levels, expression of the two miRNAs correlates with the increase in p53, and blocking of these miRNAs during the oscillations reduces the p53 pulses (Zhang et al., 2013). Hence, miR-143 and miR-145 are important for the equilibrium that maintains these pulses. "
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    ABSTRACT: p53 is a transcription factor that governs numerous stress response pathways within the cell. Maintaining the right levels of p53 is crucial for cell survival and proper cellular homeostasis. The tight regulation of p53 involves many cellular components, most notably its major negative regulators Mdm2 and Mdm4, which maintain p53 protein amount and activity in tight check. microRNAs (miRNAs) are small non-coding RNAs that target specific mRNAs to translational arrest and degradation. miRNAs are also key components of the normal p53 pathway, joining forces with Mdm2 and Mdm4 to maintain proper p53 activity. Here we review the current knowledge of miRNAs targeting Mdm2 and Mdm4, and their importance in different tissues and in pathological states such as cancer. In addition, we address the role of Alu sequences—highly abundant retroelements spread throughout the human genome, and their impact on gene regulation via the miRNA machinery. Alus occupy a significant portion of genes' 3′UTR, and as such they have the potential to impact mRNA regulation. Since Alus are primate-specific, they introduce a new regulatory layer into primate genomes. Alus can influence and alter gene regulation, creating primate-specific cancer-preventive regulatory mechanisms to sustain the transition to longer life span in primates. We review the possible influence of Alu sequences on miRNA functionality in general and specifically within the p53 network.
    Journal of Molecular Cell Biology 05/2014; 6(3):192-197. DOI:10.1093/jmcb/mju020 · 6.77 Impact Factor
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    • "Thus the decreased expression of miR-145 in these cells may be associated with the increased infiltration of astrocytic tumors. miR-145 has been shown to act as a tumor suppressor in various cellular systems by decreasing cell growth [25], apoptosis [51] and angiogenesis [52]. In addition, miR-145 has been reported to affect cell migration, invasion and metastasis in various types of tumors by targeting distinct cellular pathways [53], [54]. "
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    ABSTRACT: Glioblastomas (GBM), the most common and aggressive type of malignant glioma, are characterized by increased invasion into the surrounding brain tissues. Despite intensive therapeutic strategies, the median survival of GBM patients has remained dismal over the last decades. In this study we examined the expression of miR-145 in glial tumors and its function in glioma cells. Using TCGA analysis and real-time PCR we found that the expression of miR-145/143 cluster was downregulated in astrocytic tumors compared to normal brain specimens and in glioma cells and glioma stem cells (GSCs) compared to normal astrocytes and neural stem cells. Moreover, the low expression of both miR-145 and miR-143 in GBM was correlated with poor patient prognosis. Transfection of glioma cells with miR-145 mimic or transduction with a lentivirus vector expressing pre-miR 145 significantly decreased the migration and invasion of glioma cells. We identified connective tissue growth factor (CTGF) as a novel target of miR-145 in glioma cells; transfection of the cells with this miRNA decreased the expression of CTGF as determined by Western blot analysis and the expression of its 3'-UTR fused to luciferase. Overexpression of a CTGF plasmid lacking the 3'-UTR and administration of recombinant CTGF protein abrogated the inhibitory effect of miR-145 on glioma cell migration. Similarly, we found that silencing of CTGF decreased the migration of glioma cells. CTGF silencing also decreased the expression of SPARC, phospho-FAK and FAK and overexpression of SPARC abrogated the inhibitory effect of CTGF silencing on cell migration. These results demonstrate that miR-145 is downregulated in glial tumors and its low expression in GBM predicts poor patient prognosis. In addition miR-145 regulates glioma cell migration by targeting CTGF which downregulates SPARC expression. Therefore, miR-145 is an attractive therapeutic target for anti-invasive treatment of astrocytic tumors.
    PLoS ONE 02/2013; 8(2):e54652. DOI:10.1371/journal.pone.0054652 · 3.23 Impact Factor
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    ABSTRACT: The MDM2 oncogene is a key negative regulator of the p53 tumor suppressor protein. MDM2 and p53 form an autoregulatory feedback loop to tightly control the proper cellular responses to various stress signals in order to prevent mutations and tumor formation. The levels and function of the MDM2 protein, an E3 ubiquitin ligase, are regulated by a wide variety of extracellular and intracellular stress signals through distinct signaling pathways and mechanisms. These signals regulate the E3 ubiquitin ligase activity of MDM2, the ability of MDM2 to interact with p53 and a number of other proteins, and the cellular localization of MDM2, which in turn impact significantly upon p53 function. This review provides an overview of the regulation of MDM2 activities by the signals and factors that regulate the MDM2 protein, including genotoxic stress signals, oncogenic activation, cell cycle transition, ribosomal stress, chronic stress, neurohormones, and microRNAs. Disruption of the proper regulation of the MDM2-p53 negative feedback loop impacts significantly upon the frequency of tumorigenesis in a host. A better understanding of the complex regulation of MDM2 and its impact upon p53 function in cells under different conditions will help to develop novel and more effective strategies for cancer therapy and prevention.
    Genes & cancer 03/2012; 3(3-4):199-208. DOI:10.1177/1947601912454734
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