Dynamic modulation of thymidylate synthase gene expression and fluorouracil sensitivity in human colorectal cancer cells.
Dynamic modulation of thymidylate synthase gene expression and fluorouracil sensitivity in human colorectal cancer cells.
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DOI：
10.1371/journal.pone.0123076
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Oda S
中科院分区：
文献类型：
--
作者：
Wakasa K;Kawabata R;Nakao S;Hattori H;Taguchi K;Uchida J;Yamanaka T;Maehara Y;Fukushima M;Oda S
生物标记物彻底改变了癌症化疗。然而，许多生物标志物候选人仍在争论中。除了临床研究外，还需要先验的实验方法。胸苷酸合成酶（TS）的表达是一个长期的候选人作为生物标志物的5-氟尿嘧啶（5-FU）治疗癌症患者。使用Tet-OFF系统和人结直肠癌细胞系DLD-1，我们首先构建了TS表达动态可控的体外系统。定量分析已经阐明，TS表达在大肠杆菌中广泛调制，并且动态范围覆盖基础水平的15倍。尽管由于强力霉素毒性而未在全动态范围内检查，但在对下调的TS表达作出反应时，AML细胞的5-FU敏感性显著增加。有趣的是，我们的体外数据表明，TS表达和细胞中的5-FU敏感性之间存在线性关系。在小鼠模型中获得的数据，使用异种移植物是高度平行的，在体外获得的。因此，我们的体外和体内观察表明，TS表达是细胞中5-FU敏感性的决定因素，至少在这种特定的遗传背景下，因此，支持TS表达作为基于5-FU的癌症化疗的生物标志物的可能性。
Biomarkers have revolutionized cancer chemotherapy. However, many biomarker candidates are still in debate. In addition to clinical studies, a priori experimental approaches are needed. Thymidylate synthase (TS) expression is a long-standing candidate as a biomarker for 5-fluorouracil (5-FU) treatment of cancer patients. Using the Tet-OFF system and a human colorectal cancer cell line, DLD-1, we first constructed an in vitro system in which TS expression is dynamically controllable. Quantitative assays have elucidated that TS expression in the transformant was widely modulated, and that the dynamic range covered 15-fold of the basal level. 5-FU sensitivity of the transformant cells significantly increased in response to downregulated TS expression, although being not examined in the full dynamic range because of the doxycycline toxicity. Intriguingly, our in vitro data suggest that there is a linear relationship between TS expression and the 5-FU sensitivity in cells. Data obtained in a mouse model using transformant xenografts were highly parallel to those obtained in vitro. Thus, our in vitro and in vivo observations suggest that TS expression is a determinant of 5-FU sensitivity in cells, at least in this specific genetic background, and, therefore, support the possibility of TS expression as a biomarker for 5-FU-based cancer chemotherapy.
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