SND1 Promotes Radioresistance in Cervical Cancer Cells by Targeting the DNA Damage Response.
SND1 Promotes Radioresistance in Cervical Cancer Cells by Targeting the DNA Damage Response.
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DOI：
10.1089/cbr.2021.0371
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发表时间：
2022-03
影响因子：
3.4
通讯作者：
Xiaoming Fu;Zhongchao Duan;Xin Lu;Yingyu Zhu;Yuanyuan Ren;Wei Zhang;Xiaoming Sun;Lin Ge;Jie Yang-
中科院分区：
文献类型：
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作者：
Xiaoming Fu;Zhongchao Duan;Xin Lu;Yingyu Zhu;Yuanyuan Ren;Wei Zhang;Xiaoming Sun;Lin Ge;Jie Yang-
背景资料：放射治疗是宫颈癌最有效的治疗策略之一，但放射抵抗介导的残留和复发肿瘤是治疗失败的主要原因。然而，肿瘤放射抵抗的机制仍然是一个谜。DNA损伤反应途径是辐射抗性的关键决定因素。本研究旨在探讨SND 1在宫颈癌放射抵抗中的作用及其机制。方法：采用改良的CRISPR/Cas9双切口基因编辑系统构建SND 1基因敲除的HeLa细胞株（HeLa-KO）。通过慢病毒转染pSil-SND 1-sh-1和pSil-SND 1-sh-2质粒构建稳定的SND 1敲低CaSki细胞系（CaSki-Ctrl、CaSki-SND 1-sh-1、CaSki-SND 1-sh-2）。结果：SND 1基因缺失可显著提高宫颈癌细胞的放射敏感性。还发现沉默SND 1促进辐射诱导的细胞凋亡。值得注意的是，SND 1功能丧失的细胞表现出低效的共济失调毛细血管扩张突变途径激活，随后损害DNA修复和G2/M检查点阻滞。此外，苏氨酸103是SND 1在DNA损伤胁迫下的重要磷酸化位点。结论：总的来说，这项研究的结果揭示了沉默SND 1或T103突变对宫颈癌细胞的有效放射增敏作用，为宫颈癌治疗的潜在治疗策略提供了新的见解。
Background: Radiotherapy is one of the most effective therapeutic strategies for cervical cancer patients, although radioresistance-mediated residual and recurrent tumors are the main cause of treatment failure. However, the mechanism of tumor radioresistance is still elusive. DNA damage response pathways are key determinants of radioresistance. The purpose of this study was to investigate the role and mechanism of SND1 in radioresistance of cervical cancer. Methods: A stable HeLa cell line with SND1 knockout (HeLa-KO) was generated through a modified CRISPR/Cas9 double-nicking gene editing system. The stable CaSki cell lines with SND1 knockdown (CaSki-Ctrl, CaSki-SND1-sh-1, CaSki-SND1-sh-2) were constructed through lentivirus transfection with the pSil-SND1-sh-1 and pSil-SND1-sh-2 plasmids. Results: It was observed that SND1 deficiency significantly increased the radiosensitivity of cervical cancer cells. It was also found that silencing SND1 promotes radiation-induced apoptosis. Significantly, the cells with a loss of SND1 function exhibited inefficient ataxia telangiectasia mutated pathway activation, subsequently impairing DNA repair and G2/M checkpoint arrest. In addition, threonine 103 is an important phosphorylation site of SND1 under DNA damaging stress. Conclusion: Collectively, the results of this study reveal a potent radiosensitizing effect of silencing SND1 or T103 mutation on cervical cancer cells, providing novel insights into potential therapeutic strategies for cervical cancer treatment.