The effect of eIF3a on anthracycline-based chemotherapy resistance by regulating DSB DNA repair
The effect of eIF3a on anthracycline-based chemotherapy resistance by regulating DSB DNA repair
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eIF3a通过调节DSB DNA修复对蒽环类化疗耐药的影响
DOI：
10.1016/j.bcp.2021.114616
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发表时间：
2021-06-03
影响因子：
5.8
通讯作者：
Yin, Ji-Ye
中科院分区：
文献类型：
--
作者：
Chen, Juan;Liu, Jun-Yan;Yin, Ji-Ye
背景资料：蒽环类抗生素是拓扑异构酶II的抑制剂，可导致DNA双链断裂，广泛用于乳腺癌的治疗。eIF 3a是真核生物翻译起始因子3（eIF 3）的最大亚基，在乳腺癌中高表达。本研究旨在探讨eIF 3a在乳腺癌DSB DNA修复中的作用及其对蒽环类药物化疗的影响。方法：采用MTT法检测乳腺癌细胞株对蒽环类药物的敏感性。进行实时逆转录酶PCR、蛋白质印迹和免疫荧光以评估基因表达水平的变化。采用彗星实验和末端连接活性实验研究eIF 3a在NHEJ修复中的作用。进行荧光素酶报告基因测定以检测LIG 4 5 ' UTR活性。结果：eIF 3a通过在翻译水平上影响LIG 4和DNA-PKcs的表达，调节DSB修复活性，增强细胞对蒽环类药物的反应性。eIF 3a水平高、LIG 4水平低或DNA-PKcs水平低的乳腺癌患者蒽环类药物化疗预后较好。结论：eIF 3a可能通过调控DSB DNA修复而影响蒽环类药物化疗的疗效。
Background: Anthracycline are inhibitors of topoisomerase II leading to DNA double strand breaks, and it is widely used for treatment of breast cancer. eIF3a is the largest subunit of eukaryotic translation initiation factor 3 (eIF3) and highly expressed in breast cancer. In this study, we investigated the role of eIF3a in DSB DNA repair and the response of breast cancer patients to anthracycline-based chemotherapy.Methods: MTT assay was used to detect anthracycline sensitivity in cell lines. Real-time reverse transcriptase PCR, western blotting and immunofluorescence were performed to assess changes in gene expression levels. Comet assay and end-joining activity assay were conducted to explore the effect of eIF3a in NHEJ repair. Luciferase reporter assay was performed to detect LIG4 5 ' UTR activity. Immunohistochemistry was used to detect eIF3a, LIG4 and DNA-PKcs expression levels in breast cancer tissues.Results: The results showed that eIF3a increased cellular response to anthracyclines by regulating DSB repair activity via influencing the expression of LIG4 and DNA-PKcs at translational level. Breast cancer patients with high level of eIF3a or low level of LIG4 or low level of DNA-PKcs had better anthracycline-based chemotherapy prognosis compared. Moreover, Combined expressions of eIF3a, LIG4 and DNA-PKcs could be better to predict PFS in breast cancer patients with anthracycline-based chemotherapy.Conclusion: Our findings suggest that eIF3a effects anthracycline-based chemotherapy response by regulating DSB DNA repair.