Global analysis of gene expression changes during retinoic acid-induced growth arrest and differentiation of melanoma: comparison to differentially expressed genes in melanocytes vs melanoma.
Global analysis of gene expression changes during retinoic acid-induced growth arrest and differentiation of melanoma: comparison to differentially expressed genes in melanocytes vs melanoma.
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DOI：
10.1186/1471-2164-9-478
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发表时间：
2008-10-11
期刊：
影响因子：
4.4
通讯作者：
Niles RM
中科院分区：
文献类型：
--
作者：
Estler M;Boskovic G;Denvir J;Miles S;Primerano DA;Niles RM
恶性黑色素瘤的发病率在过去十年中显著增加。这些恶性肿瘤中的一些对全反式维甲酸（RA）的生长抑制和促分化作用敏感。负责RA在黑色素瘤中的生物活性的分子变化还没有很好地理解。在对B16小鼠黑色素瘤细胞进行4-48小时RA处理期间连续的整体基因表达变化的分析中，我们发现RA增加了757个基因的表达并降低了737个基因的表达。我们还比较了非恶性melan-a小鼠黑素细胞和B16黑色素瘤细胞之间的基因表达谱（无RA处理）。使用相同的统计检验，我们发现1495个基因在melan-a中的表达显著高于B16细胞，2054个基因在melan-a中的表达显著低于B16细胞。通过交叉这两个基因集，我们发现了一组共有的233个基因，其RNA水平在B16和melan-a细胞之间存在显著差异，并且其表达被RA处理改变。在这一组中，RA治疗改变了203（87%）基因的表达朝着黑色素-a的表达水平。此外，分层聚类显示，在RA治疗48小时后，203个基因的表达与melan-a基因集的关系比任何其他RA治疗时间点更密切。对203个基因集的功能分析表明，RA降低了编码参与细胞分裂/细胞周期、DNA复制、重组和修复以及转录调节的蛋白质的mRNA的表达。相反，它刺激参与细胞间信号传导、细胞粘附和细胞分化/胚胎发育的基因。对203个基因集的通路分析揭示了四个主要的连接中心：CDC 2、CHEK 1、CDC 45 L和MCM 6。我们对B16黑色素瘤细胞48小时RA处理和未处理的B16与melan-a数据集的常见基因的分析表明，RA“正常化”了参与能量代谢、DNA复制、DNA修复和分化的基因的表达。这些结果与已知的RA的生长抑制和促分化作用是一致的。通路分析表明，CDC 2、CHEK 1、CDC 45 L和MCM 6是介导RA在B16黑色素瘤细胞中的生物学活性的关键参与者。
The incidence of malignant melanoma has significantly increased over the last decade. Some of these malignancies are susceptible to the growth inhibitory and pro-differentiating effects of all-trans-retinoic acid (RA). The molecular changes responsible for the biological activity of RA in melanoma are not well understood. In an analysis of sequential global gene expression changes during a 4–48 h RA treatment of B16 mouse melanoma cells, we found that RA increased the expression of 757 genes and decreased the expression of 737 genes. We also compared the gene expression profile (no RA treatment) between non-malignant melan-a mouse melanocytes and B16 melanoma cells. Using the same statistical test, we found 1495 genes whose expression was significantly higher in melan-a than in B16 cells and 2054 genes whose expression was significantly lower in melan-a than in B16 cells. By intersecting these two gene sets, we discovered a common set of 233 genes whose RNA levels were significantly different between B16 and melan-a cells and whose expression was altered by RA treatment. Within this set, RA treatment altered the expression of 203 (87%) genes toward the melan-a expression level. In addition, hierarchical clustering showed that after 48 h of RA treatment expression of the 203 genes was more closely related to the melan-a gene set than any other RA treatment time point. Functional analysis of the 203 gene set indicated that RA decreased expression of mRNAs that encode proteins involved in cell division/cell cycle, DNA replication, recombination and repair, and transcription regulation. Conversely, it stimulated genes involved in cell-cell signaling, cell adhesion and cell differentiation/embryonic development. Pathway analysis of the 203 gene set revealed four major hubs of connectivity: CDC2, CHEK1, CDC45L and MCM6. Our analysis of common genes in the 48 h RA-treatment of B16 melanoma cells and untreated B16 vs. melan-a data set show that RA "normalized" the expression of genes involved in energy metabolism, DNA replication, DNA repair and differentiation. These results are compatible with the known growth inhibitory and pro-differentiating effects of RA. Pathway analysis suggests that CDC2, CHEK1, CDC45L and MCM6 are key players in mediating the biological activity of RA in B16 melanoma cells.
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影响因子：
11.4
作者：
DETHE, H;MARCHIO, A;DEJEAN, A
通讯作者：
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影响因子：
64.8
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3.7
作者：
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作者：
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Naevi中的细胞衰老和黑色素瘤中的永生化：P16的作用？
影响因子：
8.8
作者：
Gray-Schopfer, V C;Cheong, S C;Chong, H;Chow, J;Moss, T;Abdel-Malek, Z A;Marais, R;Wynford-Thomas, D;Bennett, D C
通讯作者：
Bennett, D C