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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    • "In addition, ionizing radiation-induced oxidative stress has been shown to play a role in altering miRNA expression[101]. The role of miRNA in the immune system and in inflammation has been reviewed in the literature[102,103]. The mechanism of epigenetic regulation in vivo is thought to be linked to inflammatory processes in the radiation response. "

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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.
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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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