MicroRNAs are post-transcriptional regulators that bind to complementary sequences on target messenger RNA transcripts (mRNAs), usually resulting in translational repression or target degradation and gene silencing 
. Recent studies suggest roles of miRNAs in responses to physiologic and pathologic stress such as DNA damage in fully developed tissues 
. DNA damage can transcriptionally induce specific miRNAs and regulate specific cellular functions or influence the expression of a subset of miRNAs by modulating miRNA processing. However, exposure to radiation causes damage to DNA, protein and lipids in mammalian cells, as well as increased mitochondria-dependent generation of reactive oxygen species (ROS), with subsequent cell cycle checkpoint arrest, apoptosis, and stress-related responses 
. The cellular response to radiation damage is complex and relies on simultaneous activation of a number of signaling networks. No obvious overlap of ionizing radiation-responsive miRNA profiles has been noted among different cells, including primary cells, cancer cells and blood cells 
.Consistent with these reports, in the present study using micro-RNA array we demonstrated that γ-radiation altered the expression of 31 miRNA species (16 downregulated and 15 upregulated) in human hematopoietic progenitor CD34+ cells and 32 miRNA species (14 downregulated and 18 upregulated) in human osteoblast cell line hFOB cells. The profiles of radiation-induced miRNA expression were completely different in CD34+ vs. hFOB cells and these cells have different radiation-toleration phenotypes. Nevertheless, Let-7 and miR-30 families were regulated by radiation in both CD34+ and hFOB cells.
Let-7 was the first known human miRNA and plays a key role in regulation of human cell development and cancer 
. Dickey et al. 
reviewed the literature on human miRNA expression in response to radiation and found that the level of Let-7s was significantly altered, either deregulated or upregulated, in different cell types after radiation. Consistent with this, our data show that Let-7f and Let-7g increased in irradiated CD34+ and hFOB cells, respectively. The effects of let-7s on radiation damage in our experimental cell model are under further investigation. Interestingly, miR-30 family members respond to radiation differently in CD34+ and hFOB cells and radiation oppositely regulated miR-30 expression in these cells: miR-30b, miR-30c and miR-30d were upregulated in CD34+ cells whereas miR-30c was downregulated in hFOB cells ().
Features of the responses of hematopoietic stem and progenitor cells (HSPC) and hematopoietic niche osteoblast cells to γ-radiation are different. Osteoblasts are relatively more radiation-resistant than HSPCs 
, and the reasons for this are not well understood. We recently reported that the novel cell stress response gene REDD1 is highly induced in mouse bone marrow osteoblastic cells (unpublished data) and human osteoblast cell line hFOB cells after γ-radiation 
. REDD1 was regulated by p53 and NFkB signaling in response to radiation and plays an important role in suppressing p21-induced cell proliferation arrest and mTOR-induced protein synthesis. These effects of REDD1 were associated with protection of osteoblast cells from radiation-induced premature senescence. In this study, we further demonstrate that REDD1 expression is not observed in fresh thawed hematopoietic progenitor CD34+ cells, however its expression increases with differentiation. The differentiated hematopoietic cells were more radiation-resistant than their precursor CD34+ cells (). Using bioinformatics analysis we found a potential binding site of miR-30 in the 3′ UTR of REDD1
gene. We decided to compare the effects of miR30c in CD34+ and hFOB cells in response to radiation, and asked whether the different features of miR-30c in CD34+ and hFOB cells were associated with their radiation resistance and REDD1 expression.
The effects of miR-30c on REDD1-induced radiation protection in CD34+ and hFOB cells were evaluated using gain and loss of miR-30c function studies. Our data showed that inhibition of miR-30c significantly enhanced endogenous and overexpressed REDD1 gene and protein in hFOB cells. On the contrary, pre-miR-30c repressed REDD1 in these cells. Effects of pre-miR 30c on inhibition of REDD1 were also observed in 14 day cultured CD34+ cells (differentiated hematopoietic cells). Thus, we demonstrate for the first time that REDD1 is a miR-30c target in human hematopoietic cells and their niche osteoblast cells. Furthermore, we addressed the functional activities of miR-30c in survival of radiation-injured CD34+ and hFOB cells. Transfection of miR-30c inhibitor produced a significant increase of clonogenicity in irradiated CD34+ cells and overexpression of miR30c resulted in hFOB cell death. The data suggest that miR-30c plays a key role in radiation-induced cell damage and that this effect may be due, at least in part, to suppression of REDD1 expression. There is abundant evidence of miR-30 in regulation of cell growth, differentiation, apoptosis and senescence in hematopoietic 
, osteoblast 
, adipocyte 
, epithelial and pancreatic cells 
through different signal transduction pathways. However, effects of miR-30 on ionizing radiation-induced cell damage have not been reported. Our data suggest that CD34+ and hFOB cells have different miRNA expression patterns after irradiation and that radiation-induced miR-30 expression in CD34+ cells may aggravate cell death. Notably, although inhibition of miR30c significantly protected CD34+ cells from radiation damage, it did not induce REDD1 expression in these cells, suggesting that other targets of miR-30c may be involved in radiation-induced stress responses of CD34+ cells. Since multiple potential targets of miRNAs have been suggested (5), validating miR-30 targets in irradiated CD34+ cells will be important to understand the roles of miR-30 in these cells after radiation injury.
There have been a number of studies examining miRNA expression in diseases and identifying specific miRNAs as novel and sensitive biomarkers for disease diagnosis. Radiotherapy is commonly used for cancer treatment and bone marrow toxicity is the dose-limiting factor for radiotherapy in cancer patients. Data from our study suggest that miR-30c plays a key role in radiation-induced hematopoietic cell damage, hence it may be a valuable biomarker of radiosensitivity of hematopoietic cells. This marker could be used to further characterize the toxic radiation doses in individual patients during clinical radiotherapy.