文章：

EPS8的缺失使非小细胞肺癌对化疗诱导的DNA损伤更敏感

Loss of EPS8 sensitizes non-small-cell lung carcinoma to chemotherapy-induced DNA damage 

原文发布日期：2023-03-17 

英文摘要：

Epidermal growth factor receptor pathway substrate number 8 (EPS8) has been reported to be critical in mediating tumor progression. However, the molecular and biological consequences of EPS8 overexpression remain unclear. Here we evaluated whether EPS8 increased DNA damage repair in non-small-cell lung carcinoma (NSCLC) cells and the mechanism of EPS8-mediated DNA damage repair which influenced chemosensitivity. Serial studies of functional experiments revealed that EPS8 knockdown inhibited cell growth, induced cell-cycle arrest and increased cisplatin therapeutic effects on NSCLC. EPS8 was found to induce DNA damage repair via upregulation of phosphorylated-ATM and downregulation of the tumor suppressor p53 and G1 cell kinase inhibitor p21. Moreover, in conjunction with cisplatin, decreasing EPS8 protein levels further increased p53 protein level and inhibited ATM signaling. Transplanted tumor studies were also performed to demonstrate that EPS8 knockdown inhibited tumor growth and sensitized tumors to cisplatin treatment. In conclusion, we have described a novel molecular mechanism through which EPS8 is likely to be involved in cancer progression and chemoresistance via DNA damage repair, indicating that EPS8 expression may influence the response to chemotherapy. Therefore, targeting EPS8 may be a potential therapeutic approach for patients with NSCLC. 

摘要翻译： 

表皮生长因子受体通路底物8号（EPS8）已被报道在介导肿瘤进展中起关键作用。然而，EPS8过表达的分子和生物学后果仍不明确。本研究评估了EPS8是否增强非小细胞肺癌（NSCLC）细胞的DNA损伤修复能力，并探讨了EPS8介导DNA损伤修复影响化疗敏感性的机制。系列功能实验研究表明，敲低EPS8可抑制细胞生长、诱导细胞周期阻滞并增强顺铂对NSCLC的治疗效果。研究发现EPS8通过上调磷酸化ATM、下调抑癌蛋白p53和G1期细胞激酶抑制因子p21来诱导DNA损伤修复。此外，在顺铂治疗基础上降低EPS8蛋白水平，可进一步增加p53蛋白表达并抑制ATM信号传导。移植瘤实验也证实敲低EPS8能抑制肿瘤生长并增强肿瘤对顺铂治疗的敏感性。总之，我们揭示了一种新型分子机制：EPS8可能通过DNA损伤修复途径参与癌症进展和化疗耐药，表明EPS8表达可能影响化疗反应。因此靶向EPS8可能成为NSCLC患者的潜在治疗策略。

原文链接：

Loss of EPS8 sensitizes non-small-cell lung carcinoma to chemotherapy-induced DNA damage