Aberrantly Expressed Timeless Regulates Cell Proliferation and Cisplatin Efficacy in Cervical Cancer.
Aberrantly Expressed Timeless Regulates Cell Proliferation and Cisplatin Efficacy in Cervical Cancer.
复制标题
DOI：
10.1089/hum.2019.080
复制
发表时间：
2019-12
影响因子：
4.2
通讯作者：
Jinhua Zhou;Yinghui Zhang;Xinwei Zou;Lingling Kuai;Li Wang;Juan Wang;F. Shen;Jinghui Hu;Xia Zhang;Ya-Ting Huang;Youguo Chen
中科院分区：
文献类型：
--
作者：
Jinhua Zhou;Yinghui Zhang;Xinwei Zou;Lingling Kuai;Li Wang;Juan Wang;F. Shen;Jinghui Hu;Xia Zhang;Ya-Ting Huang;Youguo Chen
Timeless是果蝇中分子时钟的调节器，与哺乳动物的癌症发展有关。目的：探讨Timeless对宫颈癌细胞增殖及顺铂敏感性的影响。通过生物信息学分析、免疫组织化学和QPCR确定无时间表达。应用ChIP测定和报告基因测定来确定促成Timeless上调的转录因子。通过体外和体内实验测定Timeless耗竭对细胞增殖和顺铂敏感性的影响。流式细胞术和β-半乳糖苷酶染色检测细胞凋亡和衰老。彗星试验、免疫荧光染色和westernblot检测DNA损伤和修复途径。Timeless在大约52.5%的宫颈癌组织中异常表达。E2 F1和E2 F4参与Timeless的转录激活。在体外和体内，无时间消耗抑制细胞增殖并增加顺铂敏感性。无时间性敲减诱导细胞凋亡和细胞衰老。在机制上，Timeless沉默导致DNA损伤，并损害宫颈癌中响应顺铂的ATR/CHK 1通路的激活。Timeless在宫颈癌中过表达，并调节细胞增殖以及顺铂敏感性，为宫颈癌中的顺铂增敏剂提供了有吸引力的靶标。
Timeless is a regulator of molecular clockwork in Drosophila and related to cancer development in mammals. To investigate the effect of Timeless on cell proliferation and cisplatin sensitivity in cervical cancer. Timeless expression was determined by bioinformatical analysis, immunohistochemistry and QPCR. ChIP assays and reporter gene assays were applied to determine transcriptional factor contributing to Timeless upregulation. The effect of Timeless depletion on cell proliferation and cisplatin sensitivity were determined by in vitro and in vivo experiments. Cell apoptosis and senescence were assessed by flow cytometry and β-galactosidase staining. DNA damage and DNA repair pathway were determined by comet assay, immunofluorescent staining and western blot. Timeless is aberrantly expressed in approximately 52.5% of cervical cancer tissues. E2F1 and E2F4 contributes to transcriptional activation of Timeless. Timeless depletion inhibits cell proliferation and increases cisplatin sensitivity in vitro and in vivo. Timeless knockdown induces cell apoptosis and cell senescence. Mechanically, Timeless silencing leads to DNA damage and impairs the activation of ATR/CHK1 pathway in response to cisplatin in cervical cancer. Timeless is overexpressed in cervical cancer and regulates cell proliferation as well as cisplatin sensitivity, presenting an attractive target for cisplatin sensitizer in cervical cancer.