miR-21-mediated Radioresistance Occurs via Promoting Repair of DNA Double Strand Breaks

Abstract

miR-21, as an oncogene that overexpresses in most human tumors, is involved in radioresistance; however, the mechanism remains unclear. Here, we demonstrate that miR-21-mediated radioresistance occurs through promoting repair of DNA double strand breaks, which includes facilitating both non-homologous end-joining (NHEJ) and homologous recombination repair (HRR). The miR-21-promoted NHEJ occurs through targeting GSK3B (a novel target of miR-21), which affects the CRY2/PP5 pathway and in turn increases DNA-PKcs activity. The miR-21-promoted HRR occurs through targeting both GSK3B and CDC25A (a known target of miR-21), which neutralizes the effects of targeting GSK3B-induced CDC25A increase because GSK3B promotes degradation of both CDC25A and cyclin D1, but CDC25A and cyclin D1 have an opposite effect on HRR. A negative correlation of expression levels between miR-21 and GSK3β exists in a subset of human tumors. Our results not only elucidate miR-21-mediated radioresistance, but also provide potential new targets for improving radiotherapy.

Delivery of Sonic Hedgehog Gene Repressed Irradiation-induced Cellular Senescence in Salivary Glands by Promoting DNA Repair and Reducing Oxidative Stress

“…5 B). Moreover, both miR-21a-5p and -3p were reported recently to promote DNA DSB repair caused by IR in tumor cells through NHEJ and homologous recombination repair (HRR) by targeting GSK3b and Cdc25a 37 . In irradiated SMGs, we confirmed that transfer of Shh gene but not control GFP gene significantly decreased the mRNA expression of GSK3b and Cdc25a compared to IR alone or the IR+Ad-GFP group (Fig.…”

“…In addition to promoting DNA repair by increasing the activity of DNA-PKcs 20 , survivin also plays an essential role in proper amphitelic kinetochore-spindle assembly, and downregulation of survivin leads to polyploidization, DNA damage and cell cycle arrest 38 ; whereas, the upregulation of survivin likely promotes escape from therapy-induced senescence directly since survivin is pivotal for cell division and is degraded by the anaphase-promoting complex/cyclosome essential for senescence 39 . miR-21 promotes repair of DNA DSB by increasing activities of DNA-PKcs and Cyclin D1 through targeting glycogen synthase kinase 3β (GSK3B) and CDC25A 37 . CHEK1 can induce the degradation of CDC25A protein to facilitate DNA DSB repair, hence the upregulation of both Chek1 and miR-21 by transient Hh activation in irradiated SMGs may synergize to promote DNA repair.…”

MicroRNA‑301a targets WNT1 to suppress cell proliferation and migration and enhance radiosensitivity in esophageal cancer cells

“…An increasing body of evidence has demonstrated that miRNAs can act as tumor promoters or suppressors to regulate various basic cellular functions (8)(9)(10). Furthermore, some studies have revealed that miRNAs directly affect radioresistance by regulating specific pathways (11), including the repair of DNA double strand breaks (12), cell cycle checkpoint activation (13), apoptosis (14) and autophagy (15). For example, Lin28-let7 regulates the radiosensitivity of human cancers through activated KRAS signaling (16).…”

MiR‐21 ameliorates age‐associated skin wound healing defects in mice

“…All mice‐related experiments were approved by the Institutional Animal Care and Use Committee of Army Military Medical University (AMMU, Chongqing, China). miR‐21 knock‐in mice were obtained as a gift from the laboratory of Dr Ya Wang . In brief, the miR‐21 sequence under the CAG promoter was knocked in the X chromosome by homologus recombination.…”

“…miR-21 knock-in mice were obtained as a gift from the laboratory of Dr Ya Wang. 26,27 In brief, the miR-21 sequence under the CAG promoter was knocked in the X chromosome by homologus recombination. The knock-in mice were initially on a mixed C57BL/6 J and 129/SvEv background and were then backcrossed with C57BL/6 J mice to the F4 generation.…”