Low doses of decitabine improve the chemotherapy efficacy against basal-like bladder cancer by targeting cancer stem cells.
Low doses of decitabine improve the chemotherapy efficacy against basal-like bladder cancer by targeting cancer stem cells.
复制标题
低剂量的地西他滨通过靶向癌症干细胞来提高针对基底样膀胱癌的化疗效果。
DOI：
10.1038/s41388-019-0799-1
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发表时间：
2019
期刊：
影响因子：
8
通讯作者：
Li Yang
中科院分区：
文献类型：
--
作者：
Wu Mingqing;Sheng Lu;Cheng Maosheng;Zhang Haojie;Jiang Yizhou;Lin Shuibin;Liang Yu;Zhu Fengyu;Liu Zhenqing;Zhang Yingyin;Zhang Xiuhong;Gao Qian;Chen Demeng;Li Jiong;Li Yang
DNA甲基化抑制剂地西他滨的低剂量治疗已被证明适用于某些类型的癌症的管理。然而，其抗肿瘤作用和机制是依赖于上下文的，并且其活性在膀胱癌治疗中从未被系统地研究过。我们使用小鼠模型、培养的细胞系和患者来源的异种移植物来证明低剂量地西他滨治疗显著增强顺铂和吉西他滨在体内和体外对基底样膀胱癌的作用。遗传谱系追踪显示，小鼠中地西他滨治疗可抑制膀胱癌干细胞群体的干性。这些效应伴随着全基因组DNA甲基化、基因再表达和关键细胞调控途径（如STAT3信号传导）的变化。这些结果表明，这种DNA去甲基化试剂是一种有前途的治疗基底细胞样膀胱癌的治疗方法。
Low dose treatment with the DNA methylation inhibitor decitabine has been shown to be applicable for the management of certain types of cancer. However, its antitumor effect and mechanisms are context dependent and its activity has never been systematically studied in bladder cancer treatment. We used mouse models, cultured cell lines and patient-derived xenografts to demonstrate that low dose decitabine treatment remarkably enhanced the effects of cisplatin and gemcitabine on basal-like bladder cancer both in vivo and in vitro. Genetic lineage tracing revealed that the stemness of a bladder cancer stem cell population was inhibited by decitabine treatment in mice. These effects were accompanied by decreases in genome-wide DNA methylation, gene re-expression, and changes in key cellular regulatory pathways such as STAT3 signaling. These results indicate that this DNA-demethylating reagent is a promising therapeutic approach for basal-like bladder cancer treatment.