Centre for Information Based Medicine, University of Newcastle, Newcastle, New South Wales, Australia.
Cancer Res. 2010 Oct 15;70(20):7918-26. doi: 10.1158/0008-5472.CAN-10-0161. Epub 2010 Aug 31.
Two of the hallmark features of melanoma are its development as a result of chronic UV radiation exposure and the limited efficacy of cisplatin in the disease treatment. Both of these DNA-damaging agents result in large helix-distorting DNA damage that is recognized and repaired by nucleotide excision repair (NER). The aim of this study was to examine the expression of NER gene transcripts, p53, and p21 in melanoma cell lines treated with cisplatin compared with melanocytes. Basal expression of all genes was greater in the melanoma cell lines compared with melanocytes. Global genome repair (GGR) transcripts showed significantly decreased relative expression (RE) in melanoma cell lines 24 hours after cisplatin treatment. The basal RE of p53 was significantly higher in the melanoma cell lines compared with the melanocytes. However, induction of p53 was only significant in the melanocytes at 6 and 24 hours after cisplatin treatment. Inhibition of p53 expression significantly decreased the expression of all the GGR transcripts in melanocytes at 6 and 24 hours after cisplatin treatment. Although the RE levels were lower with p53 inhibition, the induction of the GGR genes was very similar to that in the control melanocytes and increased significantly across the time points. The findings from this study revealed reduced GGR transcript levels in melanoma cells 24 hours after cisplatin treatment. Our findings suggest a possible mechanistic explanation for the limited efficacy of cisplatin treatment and the possible role of UV light in melanoma.
它是由慢性紫外线辐射暴露引起的，以及顺铂在疾病治疗中的疗效有限。这两种 DNA 损伤剂都会导致大的螺旋扭曲 DNA 损伤，被核苷酸切除修复（NER）识别和修复。本研究旨在研究顺铂处理的黑色素瘤细胞系与黑素细胞中 NER 基因转录本、p53 和 p21 的表达。与黑素细胞相比，所有基因在黑色素瘤细胞系中的基础表达都更高。顺铂处理 24 小时后，全基因组修复（GGR）转录本的相对表达（RE）显著降低。与黑素细胞相比，p53 的基础 RE 在黑色素瘤细胞系中显著更高。然而，p53 的诱导仅在顺铂处理后 6 和 24 小时在黑素细胞中显著。抑制 p53 表达可显著降低顺铂处理后 6 和 24 小时黑素细胞中所有 GGR 转录本的表达。尽管抑制 p53 表达后 RE 水平较低，但 GGR 基因的诱导与对照黑素细胞非常相似，并随着时间点的增加而显著增加。本研究的结果显示，顺铂处理 24 小时后黑色素瘤细胞中的 GGR 转录本水平降低。我们的发现为顺铂治疗疗效有限提供了一种可能的机制解释，并为紫外线在黑色素瘤中的可能作用提供了依据。
