CDK6 inhibition targeted by miR-378a-3p protects against intestinal injury induced by ionizing radiation
CDK6 inhibition targeted by miR-378a-3p protects against intestinal injury induced by ionizing radiation
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miR-378a-3p 靶向的 CDK6 抑制可防止电离辐射引起的肠道损伤
DOI：
10.1016/j.bbrc.2020.07.093
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发表时间：
2020-10-20
影响因子：
3.1
通讯作者：
Shao, Chunlin
中科院分区：
文献类型：
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作者：
Chu, Xiaofei;Zheng, Wang;Shao, Chunlin
放化疗是腹部肿瘤治疗的一种常用方法。然而，放射诱发的肠道综合征是导致放疗预后不良的主要因素。在这项工作中，我们发现miR-378a-3p在全腹部照射后的小鼠小肠中显著上调。MiR-378a-3p基因敲除(或过表达)可增加(或降低)小肠癌细胞HIEC和FHs-74-Int的放射敏感性。彗星实验和g-H_2AX染色显示miR-378a-3p通过减少DNA损伤在小肠细胞和组织中的累积而发挥其辐射防护作用。在机制上，miR-378a-3p可以通过互补序列与CDK6的30个非编码区相互作用，从而抑制CDK6在小肠细胞中的表达。营救性实验表明，CDK6的强制表达可取消miR-378a-3p过表达对细胞辐射敏感性和DNA损伤积累的抑制。综上所述，我们的结果首次揭示了miR-378a-3p通过靶向CDK6来调节小肠的辐射敏感性和DNA损伤反应。MIR-378a-3p有望成为腹癌的生物标志物和放射防护靶点。(C)2020 Elsevier Inc.保留所有权利。
Radiotherapy combined with chemotherapy is a common modality in abdominal cancer treatment. However, intestinal syndrome induced by radiation is a main factor leading to the poor prognosis of radiotherapy. In this work, we found that miR-378a-3p was markedly up-regulated in the small intestines of mice after total abdominal irradiation. Knocking-down (or overexpression) of miR-378a-3p increased (or decreased) the radiosensitivity of the small intestine cells HIEC and FHs-74-Int. Comet assay and g-H2AX staining demonstrated that miR-378a-3p exerted its radioprotective function by reducing the accumulation of DNA damage in the cells and tissues of the small intestines. Mechanistically, miR-378a-3p could interact with the 30 UTR of CDK6 through complementary sequences and thus inhibited CDK6 expression in the small intestine cells. Rescue experiments suggested that the repression of miR-378a-3p overexpression on cell radiosensitivity and DNA damage accumulation was abrogated by the forced expression of CDK6. In summary, our results revealed for the first time that miR-378a-3p regulated the radiosensitivity and DNA damage response of small intestines by targeting CDK6. MiR-378a-3p may serve as a promising biomarker and radioprotective target in abdominal cancer. (C) 2020 Elsevier Inc. All rights reserved.