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M. Hu et al.
ulated by irradiation via the EGFR/STAT3 and ATM path- ways,48,49 which is line with our data (Online Supplementary Figure S7D). However, the role of miR-21 in HSC in the context of irradiation remains obscure. In the present study, we discovered that miR-21 can prevent HSC from irradiation-induced DNA damage through activating the NF-κB pathway, which is consistent with a recent finding that miR-21 promotes hematopoietic cell survival after exposure to irradiation.50 Moreover, our study revealed that miR-21 may also be involved in thrombopoietin- mediated non-homologous end junction repair in HSC. Nevertheless, we do not deny that there may be other NF- κB-independent mechanisms that mediate the radiopro- tective effects of miR-21 in HSC.47
On the other hand, some studies have reported that miR-21 is also a downstream target gene of the NF-κB pathway.44 Indeed, overexpression of PDCD4 or treatment with a NF-κB inhibitor (QNZ) significantly inhibited the expression of miR-21 in HSC from normal WT mice (data not shown). These findings led us to hypothesize that there may be a positive regulatory feedback loop that regulates HSC function.
In summary, our findings reveal a novel function of miR-21 as an important regulator of HSC homeostasis via modulation of the NF-κB pathway by targeting PDCD4,
thereby extending our understanding of the biological function of miR-21. At the same time, we demonstrate that targeting miR-21 may be a promising avenue for safe- guarding HSC against irradiation damage.
Disclosures
No conflicts of interest to disclose.
Contributions
MH designed the study, performed experiments, analyzed data and wrote the paper; YL, ZZ and HZ performed experi- ments and analyzed data. SC, YQ, YX, FC and YT participat- ed in the animal experiments and data analysis; MC, CD and MS contributed to the in vitro experiments; FW and YS partici- pated in the initial experimental design and discussed the manu- script; JW and SW conceived and supervised the study, and revised the manuscript.
Acknowledgments
We thank Prof. Jinyong Wang for the gift of the CD45.1 mice, Yang Liu for technical support in flow cytometry, and Liting Wang for technical assistance in immunofluorescence microscopy. This work was supported by grants from the National Natural Science Fund of China (n. 81725019, 81930090, 81573084, 81500087) and the Scientific Research Project of PLA (AWS16J014).
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