REV3L modulates cisplatin sensitivity of non-small cell lung cancer H1299 cells
REV3L modulates cisplatin sensitivity of non-small cell lung cancer H1299 cells
复制标题
REV3L调节非小细胞肺癌H1299细胞的顺铂敏感性
DOI：
10.3892/or.2015.4121
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发表时间：
2015-09-01
期刊：
影响因子：
4.2
通讯作者：
Zhang, Shuyu
中科院分区：
文献类型：
--
作者：
Wang, Wenjie;Sheng, Wenjiong;Zhang, Shuyu
肺癌仍然是全球癌症相关死亡的主要原因，非小细胞肺癌（NSCLC）约占所有肺癌病例的80-85%。顺铂在人类肺癌的管理中起着重要作用。跨损伤DNA合成（TLS）参与DNA损伤修复。DNA聚合酶（Polzeta）能够介导DNA复制绕过DNA损伤，这被认为与化疗耐药有关。REV 3L是Pol的催化亚基由于其在跨损伤DNA合成中的关键作用，REV 3L是否调节NSCLC细胞中的顺铂反应仍不清楚。本研究建立了REV 3L过表达和沉默的H1299细胞系。有报道表明顺铂通过募集Sp1到其启动子来诱导REV 3L的表达。当测量细胞从铂化质粒表达荧光素酶的能力时，获得了类似的结果。报告基因与REV 3L过表达载体或REV 3L加REV 7 L的共转染显著增强了报告基因活性。顺铂暴露后，shRNA-REV 3L H1299细胞的核凝聚和碎片比shRNA-NC H1299细胞更明显，表明REV 3L过表达消除了顺铂诱导的DNA损伤。此外，REV 3L的强制表达赋予H1299细胞对顺铂的抗性，而REV 3L的敲低使H1299细胞中的顺铂功效敏感。综上所述，我们证明了REV 3L的抑制使肺癌H1299细胞对顺铂治疗敏感。因此，REV 3L可能成为NSCLC化疗的新靶点。
Lung cancer remains the leading cause of cancer-related mortality worldwide and non-small cell lung cancer (NSCLC) accounts for approximately 80-85% of all cases of lung cancer. Cisplatin plays a significant role in the management of human lung cancer. Trans lesion DNA synthesis (TLS) is involved in DNA damage repair. DNA polymerase (Pol zeta) is able to mediate the DNA replication bypass of DNA damage, which is suggested to be involved in chemoresistance. REV3L is the catalytic subunit of Pol Due to its critical role in translesion DNA synthesis, whether REV3L modulates cisplatin response in NSCLC cells remains unknown. In this study, REV3L overexpression and silencing H1299 cell lines were established. The reports showed that cisplatin induced the expression of REV3L by recruiting Sp1 to its promoter. Similar results were obtained when the ability of the cells to express luciferase from a platinated plasmid was measured. Co-transfection of the reporter with the REV3L overexpression vector or REV3L plus REV7L significantly enhanced the reporter activity. Nuclear condensation and fragmentation of shRNA-REV3L H1299 cells were more pronounced than shRNA-NC H1299 cells after cisplatin exposure, indicating that REV3L overexpression abolished cisplatin-induced DNA damage. Moreover, a forced expression of REV3L conferred the resistance of H1299 cells to cisplatin, whereas the knockdown of REV3L sensitized cisplatin efficacy in H1299 cells. Taken together, we demonstrated that inhibition of REV3L sensitized lung cancer H1299 cells to cisplatin treatment. Thus, REV3L may be a novel target for the chemotherapy of NSCLC.