期刊
HUMAN GENE THERAPY
卷 31, 期 5-6, 页码 385-395出版社
MARY ANN LIEBERT, INC
DOI: 10.1089/hum.2019.080
关键词
cervical cancer; cisplatin sensitivity; proliferation; Timeless
资金
- National Natural Science Foundation of China [81772773, 81672560, 81302275]
- Jiangsu Provincial Medical Youth Talent [QNRC2016753]
- Project of Jiangsu Provincial Maternal and Child Health Association [FYX201709]
- Jiangsu Key Discipline of Human Assisted Reproduction Medicine Foundation [FXK201749]
- Jiangsu Provincial Medical Talent of the Project of Invigorating Healthcare through Science, Technology and Education [ZDRCA2016044]
Timeless is a regulator of molecular clockwork in Drosophila and related to cancer development in mammals. This study aimed to investigate the effect of Timeless on cell proliferation and cisplatin sensitivity in cervical cancer. Timeless expression was determined by bioinformatics analysis, immunohistochemistry, and quantitative polymerase chain reaction (qPCR). Chromatin immunoprecipitation assays and reporter gene assays were applied to determine the transcriptional factor contributing to Timeless upregulation. The effects of Timeless depletion on cell proliferation and cisplatin sensitivity were determined through in vitro and in vivo experiments. Cell apoptosis and senescence were assessed by flow cytometry and beta-galactosidase staining. DNA damage and DNA repair pathways were determined by comet assay, immunofluorescent staining, and Western blot analysis. Timeless is aberrantly expressed in similar to 52.5% of cervical cancer tissues. E2F1 and E2F4 contribute to the transcriptional activation of Timeless. Timeless depletion inhibits cell proliferation and increases cisplatin sensitivity in vitro and in vivo. Knockdown of Timeless induces cell apoptosis and cell senescence. Mechanically, Timeless silencing leads to DNA damage and impairs the activation of the ATR/CHK1 pathway in response to cisplatin in cervical cancer. Timeless is overexpressed in cervical cancer and regulates cell proliferation and cisplatin sensitivity, presenting an attractive target for cisplatin sensitizer in cervical cancer.
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