5-氟尿嘧啶对人结肠癌KM12C细胞中c-Myc的下调作用及血管生成抑制剂血小板反应蛋白-1的诱导作用
Down regulation of c-Myc and induction of an angiogenesis inhibitor, thrombospondin-1, by 5-FU in human colon cancer KM12C cells.
作者信息
Zhao Hong-Ye, Ooyama Akio, Yamamoto Masatatsu, Ikeda Ryuji, Haraguchi Misako, Tabata Sho, Furukawa Tatsuhiko, Che Xiao-Fang, Iwashita Ken-ichi, Oka Toshinori, Fukushima Masakazu, Nakagawa Masayuki, Ono Mayumi, Kuwano Michihiko, Akiyama Shin-ichi
机构信息
Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima, Japan.
出版信息
Cancer Lett. 2008 Oct 18;270(1):156-63. doi: 10.1016/j.canlet.2008.04.045. Epub 2008 Jun 25.
5-FU is commonly used for treatment of various solid tumors including colon carcinoma. We have previously demonstrated that Egr-1 induced by 5-FU enhanced TSP-1 expression in human colon cancer KM12C cells. In this study, a Genechip analysis of KM12C cells treated with 5-FU revealed down-regulation of 924 genes and up-regulation of 460 genes. The decreased expression of c-Myc mRNA and phosphorylated c-Myc were detected and confirmed by RT-PCR and immunoblotting. Since 5-FU induced the expression of TSP-1, we examined the effect of c-Myc on the TSP-1 promoter. Deletion of the TSP-1 promoter region in which binding sites for c-Myc reside had no effect on the TSP-1 promoter activity induced by 5-FU. Meanwhile, 5-FU dose-dependently decreased the expression of miR-17-92 cluster. These findings suggest that 5-FU decreased the expression of c-Myc and consequently miR-17-92 cluster and increased the expression of TSP-1 mRNA.
5-氟尿嘧啶常用于治疗包括结肠癌在内的各种实体瘤。我们之前已经证明，5-氟尿嘧啶诱导的早期生长反应因子-1（Egr-1）可增强人结肠癌KM12C细胞中血小板反应蛋白-1（TSP-1）的表达。在本研究中，对用5-氟尿嘧啶处理的KM12C细胞进行基因芯片分析，结果显示924个基因表达下调，460个基因表达上调。通过逆转录聚合酶链反应（RT-PCR）和免疫印迹检测并证实了c-Myc信使核糖核酸（mRNA）表达降低以及磷酸化c-Myc水平降低。由于5-氟尿嘧啶诱导了TSP-1的表达，我们检测了c-Myc对TSP-1启动子的影响。缺失c-Myc结合位点所在的TSP-1启动子区域对5-氟尿嘧啶诱导的TSP-1启动子活性没有影响。同时，5-氟尿嘧啶呈剂量依赖性降低miR-17-92簇的表达。这些发现表明，5-氟尿嘧啶降低了c-Myc的表达，进而降低了miR-17-92簇的表达，并增加了TSP-1 mRNA的表达。
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