Takahashi Yasuo, Nagata Toshihito, Ishii Yukimoto, Ikarashi Masahito, Ishikawa Koichi, Asai Satoshi
Medical Research Center, Nihon University School of Medicine, Itabashi, Tokyo 173-8610, Japan.
Oncol Rep. 2002 Jan-Feb;9(1):75-9.
Despite the wide use of 5-fluorouracil (5-FU) for colon cancer, the genes regulating its cytotoxic effect are poorly understood. We used a high-density oligonucleotide microarray representing approximately 7000 genes to determine changes in gene expression caused by 5-FU treatment in the colon cancer cell line, SW620. The microarray showed that the most strongly up-regulated gene by 5-FU was vitamin D3 up-regulated protein 1 (VDUP1), an interesting stress response gene, which was originally reported as a vitamin D3 inducible gene in HL-60. TaqMan RT-PCR assay confirmed that VDUP1 gene expression was significantly increased after 24 h of 5-FU treatment compared with untreated control (p<0.01). Moreover, the expression of vitamin D3 receptor, thymidylate synthase (TS), and E2F1 did not change within 24 h of 5-FU treatment, suggesting a different gene-regulatory pathway from that of VDUP1. Recent studies have gradually clarified the potential role of VDUP1 via interaction with TRX in an anti-tumor effect. Therefore, VDUP1 not only may be induced by stress response as a result of 5-FU cytotoxicity, but may also play a key role in 5-FU cytotoxicity in colon cancers. Our experiment using a microarray and TaqMan RT-PCR assay, together with previous reports, provides new insight into a potential mechanism of 5-FU cytotoxicity.
尽管5-氟尿嘧啶（5-FU）在结肠癌治疗中被广泛应用，但其细胞毒性作用的调控基因却鲜为人知。我们使用了一个代表约7000个基因的高密度寡核苷酸微阵列，来确定5-FU处理对结肠癌细胞系SW620基因表达的影响。微阵列显示，5-FU上调最显著的基因是维生素D3上调蛋白1（VDUP1），这是一个有趣的应激反应基因，最初在HL-60细胞中被报道为维生素D3诱导基因。TaqMan RT-PCR检测证实，与未处理的对照组相比，5-FU处理24小时后VDUP1基因表达显著增加（p<0.01）。此外，在5-FU处理的24小时内，维生素D3受体、胸苷酸合成酶（TS）和E2F1的表达没有变化，这表明其基因调控途径与VDUP1不同。最近的研究逐渐阐明了VDUP1通过与TRX相互作用在抗肿瘤作用中的潜在作用。因此，VDUP1不仅可能因5-FU细胞毒性导致的应激反应而被诱导，还可能在结肠癌的5-FU细胞毒性中起关键作用。我们使用微阵列和TaqMan RT-PCR检测的实验，以及之前的报道，为5-FU细胞毒性的潜在机制提供了新的见解。
