MYC predetermines the sensitivity of gastrointestinal cancer to antifolate drugs through regulating TYMS transcription
文献类型：期刊论文
| 作者 | Liu, Tingting1,2; Han, Yumin1,2; Yu, Chunhong1,2; Wang, Changxu1,2; Chen, Xiaomin1,2; Wang, Xiang1,2; Shen, Jiayan1,2; Zhang, Yongfeng1,2; Lang, Jing-Yu1,2; Ji, Yan2 |
| 刊名 | EBIOMEDICINE
 |
| 出版日期 | 2019 |
| 卷号 | 48期号:-页码:289-300 |
| 关键词 | Thymidylate synthase Raltitrexed MYC NIPBL Genome-scale CRISPR-Cas9 knockout screening |
| ISSN号 | 2352-3964 |
| DOI | 10.1016/j.ebiom.2019.10.003 |
| 文献子类 | Article |
| 英文摘要 | Background: Thymidylate synthase (TYMS) is a successful chemotherapeutic target for anticancer therapy. Numerous TYMS inhibitors have been developed and used for treating gastrointestinal cancer now, but they have limited clinical benefits due to the prevalent unresponsiveness and toxicity. It is urgent to identify a predictive biomarker to guide the precise clinical use of TYMS inhibitors. Methods: Genome-scale CRISPR-Cas9 knockout screening was performed to identify potential therapeutic targets for treating gastrointestinal tumours as well as key regulators of raltitrexed (RTX) sensitivity. Cell-based functional assays were used to investigate how MYC regulates TYMS transcription. Cancer patient data were used to verify the correlation between drug response and MYC and/or TYMS mRNA levels. Finally, the role of NIPBL inactivation in gastrointestinal cancer was evaluated in vitro and in vivo. Findings: TYMS is essential for maintaining the viability of gastrointestinal cancer cells, and is selectively inhibited by RTX. Mechanistically, MYC presets gastrointestinal cancer sensitivity to RTX through upregulating TYMS transcription, supported by TCGA data showing that complete response cases to TYMS inhibitors had significantly higher MYC and TYMS mRNA levels than those of progressive diseases. NIPBL inactivation decreases the therapeutic responses of gastrointestinal cancer to RTX through blocking MYC. Interpretation: Our study unveils a mechanism of how TYMS is transcriptionally regulated by MYC, and provides rationales for the precise use of TYMS inhibitors in the clinic. (C) 2019 The Authors. Published by Elsevier B.V. |
| 学科主题 | Oncology ; Cell Biology |
| WOS关键词 | SISTER-CHROMATID COHESION ; THYMIDYLATE SYNTHASE ; GENE-EXPRESSION ; PHASE-III ; GENOME ; COMBINATION ; RESISTANCE ; INHIBITORS ; MUTATIONS ; MECHANISM |
| 语种 | 英语 |
| CSCD记录号 | CSCD:31648989 |
| WOS记录号 | WOS:000493830800034 |
| 出版者 | ELSEVIER |
| 版本 | 出版稿 |
| 源URL | [http://202.127.25.144/handle/331004/1219]  |
| 专题 | 中国科学院上海生命科学研究院营养科学研究所 |
| 作者单位 | 1.Shanghai Jiao Tong Univ, Sch Med, Inst Hlth Sci, CAS Key Lab Tissue Microenvironm & Tumor, Shanghai 200031, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China; 3.Shanghai Jiao Tong Univ, Sch Med, Inst Hlth Sci, Bioinformat Core, Shanghai 200031, Peoples R China, |
| 推荐引用方式 GB/T 7714 | Liu, Tingting,Han, Yumin,Yu, Chunhong,et al. MYC predetermines the sensitivity of gastrointestinal cancer to antifolate drugs through regulating TYMS transcription[J]. EBIOMEDICINE,2019,48(-):289-300. |
| APA | Liu, Tingting.,Han, Yumin.,Yu, Chunhong.,Wang, Changxu.,Chen, Xiaomin.,...&,.(2019).MYC predetermines the sensitivity of gastrointestinal cancer to antifolate drugs through regulating TYMS transcription.EBIOMEDICINE,48(-),289-300. |
| MLA | Liu, Tingting,et al."MYC predetermines the sensitivity of gastrointestinal cancer to antifolate drugs through regulating TYMS transcription".EBIOMEDICINE 48.-(2019):289-300. |
入库方式： OAI收割
来源：上海营养与健康研究所
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