The mir-34 microRNA is required for the DNA damage response in vivo in C. elegans and in vitro in human breast cancer cells

Abstract

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.

Metformin‐mediated increase in DICER1 regulates microRNA expression and cellular senescence

“…An age‐associated alteration in miR‐34 occurs in the mouse and overexpression of miR‐34 in Drosophila extends lifespan (Li et al ., 2011; Liu et al ., 2012). miR‐34 may play an important role in responding to DNA damage and also in protecting against osteoporosis and neurodegeneration (Kato et al ., 2009; Liu et al ., 2012; Krzeszinski et al ., 2014). Metformin has been shown to upregulate miR‐34a in cancer cells in culture (Do et al ., 2014).…”

mir-35 is involved in intestine cell G1/S transition and germ cell proliferation in C. elegans

“…These small RNAs regulate gene expression mainly through degradation of target mRNAs [2], termination of translation [3], and chromatin modification [4]. In C. elegans, there are currently about 170 miRNA genes listed in the miRBase sequence database (http:// www.mirbase.org); however, only a few have been studied in detail [5][6][7][8][9][10][11][12][13][14]. Because deleting most miRNAs individually does not lead to any overt phenotypes/ abnormalities in development and differentiation [15], it has been a popular accord that functional redundancy of different miRNAs (miRNAs share the same or have diverse and overlapping target mRNAs) may contribute to the limited progress of miRNA study in the worm.…”

MicroRNAs as potential cancer therapeutics

“…We have also shown recently that the exogenous addition of miR-34 protects breast cancer cells from radiation-induced cell death and that lowering the level of miR-34a with anti-miR radiosensitized the cells (Kato et al, 2009). Significantly, works by Meng et al (2006) and Weidhaas et al (2007) also showed that chemotherapy and radiation treatment alter miRNA expression, perhaps as part of the cellular damage repair pathway.…”