The mir-34 microRNA is required for the DNA damage response

Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520, USA.
Oncogene (Impact Factor: 8.46). 06/2009; 28(25):2419-24. DOI: 10.1038/onc.2009.106
Source: PubMed


MicroRNAs (miRNAs) are important regulators of cell fate determination and homeostasis. Expression of these small RNA genes is tightly regulated during development and in normal tissues, but they are often misregulated in cancer. MiRNA expression is also affected by DNA damaging agents, such as radiation. In particular, mammalian miR-34 is upregulated by p53 in response to radiation, but little is known about the role of this miRNA in vivo. Here we show that Caenorhabditis elegans with loss-of-function mutations in the mir-34 gene have an abnormal cellular survival response to radiation; these animals are highly radiosensitive in the soma and radioresistant in the germline. These findings show a role for mir-34 in both apoptotic and non-apoptotic cell death in vivo, much like that of cep-1, the C. elegans p53 homolog. These results have been additionally validated in vitro in breast cancer cells, wherein exogenous addition of miR-34 alters cell survival post-radiation. These observations confirm that mir-34 is required for a normal cellular response to DNA damage in vivo resulting in altered cellular survival post-irradiation, and point to a potential therapeutic use for anti-miR-34 as a radiosensitizing agent in p53-mutant breast cancer.

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    • "This attenuation has been partly attributed to the modulatory role of miR-r-34 on HuR, Bcl-2, Sirt1 MAGE-A and p53 expressions (Kojima et al., 2010; Weeraratne et al., 2011). As cell models have shown the efficacy of miR-34 treatment, there are few animal studies which have shown that vector-based delivery of miR-34 has therapeutic potential (Hu et al., 2010; Kato et al., 2009; Kota et al., 2009; Kumar et al., 2008; Wiggins et al., 2010; Yan et al., 2011). However, the ultimate therapeutic benefits of miR-34 in vivo depend largely on the delivery system. "
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    ABSTRACT: MicroRNA-34 is involved in pathogenesis in cancer by targeting different tumor-related genes. It could be a biomarker for predicting the prognosis of patients with cancer. In addition, miR-34 is involved in the tumor angiogenesis. Understanding the mechanism of the miR-34 in cancer and tumor angiogenesis will open horizons for development of anti-cancer and anti-angiogenesis drugs.
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    • "One of the upregulated miRNAs identified in the current study was miR-30a-5p, which has been reported to modulate cell growth by targeting the denticleless protein homolog, a gene implicated in S phase and UVB-induced growth arrest (28). miR-34a-5p and miR-34b-5p, which were upregulated 1.6- and 1.8-fold in the current study, respectively, are induced by DNA damage in various types of cell (29,30), and by p53, which is activated by DNA break-induced ataxia telangiectasia mutated activation (29). Overall, the results of the current study indicate that, in nHDPs, UVB regulates specific miRNAs in order to regulate cell growth and death. "
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    ABSTRACT: Ultraviolet (UV) radiation impairs intracellular functions by directly damaging DNA and by indirectly generating reactive oxygen species (ROS), which induce cell cycle arrest and apoptosis. UV radiation can also alter gene expression profiles, including those of mRNA and microRNA (miRNA). The effects of UV radiation on cellular functions and gene expression have been widely documented in human skin cells such as keratinocytes, melanocytes and dermal fibroblasts, but the effect it has on other types of skin cell such as dermal papilla cells, which are crucial in the induction of hair follicle growth, remains unknown. In the current study, the effect of UV radiation on physiological changes and miRNA‑based expression profiles in normal human dermal papilla cells (nHDPs) was investigated. UVB radiation of ≥50 mJ/cm2 displayed high cytotoxicity and apoptosis in a dose‑dependent manner. In addition, ROS generation was exhibited in UVB‑irradiated nHDPs. Furthermore, using miRNA microarray analysis, it was demonstrated that the expression profiles of 42 miRNAs in UVB‑irradiated nHDPs were significantly altered compared with those in the controls (35 upregulated and 7 downregulated). The biological functions of the differentially expressed miRNAs were studied with gene ontology analysis to identify their putative target mRNAs, and were demonstrated to be involved in cell survival‑ and death‑related functions. Overall, the results of the present study provide evidence that miRNA‑based cellular mechanisms may be involved in the UVB‑induced cellular response in nHDPs.
    Full-text · Article · Jul 2014 · Molecular Medicine Reports
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    • "Of clinical importance, the expression of distinct miRNAs seem to be associated with the prognosis of the efficacy of therapeutic interventions, including radiotherapy [5]. In fact, miRNAs have been shown to modulate the radiosensitivity of lung cancer cells, breast cancer cells in vitro and Caenorhabditis elegans in vivo[6,7]. Moreover, normal cells show altered levels of miRNAs in response to ionizing radiation [8]. "
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    ABSTRACT: Purpose Exposure to radiation provokes cellular responses, which are likely regulated by gene expression networks. MicroRNAs are small non-coding RNAs, which regulate gene expression by promoting mRNA degradation or inhibiting protein translation. The expression patterns of both mRNA and miRNA during the radiation-induced lung injury (RILI) remain less characterized and the role of miRNAs in the regulation of this process has not been studied. The present study sought to evaluate miRNA and mRNA expression profiles in the rat lung after irradiation. Methods and materials Male Wistar rats were subjected to single dose irradiation with 20 Gy using 6 MV x-rays to the right lung. (A dose rate of 5 Gy/min was applied). Rats were sacrificed at 3, 12 and 26 weeks after irradiation, and morphological changes in the lung were examined by haematoxylin and eosin. The miRNA and mRNA expression profiles were evaluated by microarrays and followed by quantitative RT-PCR analysis. Results A cDNA microarray analysis found 2183 transcripts being up-regulated and 2917 transcripts down-regulated (P ≤ 0.05, ≥2.0 fold change) in the lung tissues after irradiation. Likewise, a miRNAs microarray analysis indicated 15 miRNA species being up-regulated and 8 down-regulated (P ≤ 0.05). Subsequent bioinformatics anal -yses of the differentially expressed mRNA and miRNAs revealed that alterations in mRNA expression following irradiation were negatively correlated with miRNAs expression. Conclusions Our results provide evidence indicating that irradiation induces alterations of mRNA and miRNA expression in rat lung and that there is a negative correlation of mRNA and miRNA expression levels after irradiation. These findings significantly advance our understanding of the regulatory mechanisms underlying the pathophysiology of radiation-induced lung injury. In summary, RILI does not develop gradually in a linear process. In fact, different cell types interact via cytokines in a very complex network. Furthermore, this study suggests that microRNAs may serve an important role in the pathogenesis of RILI and that understanding their role in RILI may have a significant effect on patient management and diagnosis in the future.
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