Riggs Penny K, Angel Joe M, Abel Erika L, DiGiovanni John
Department of Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, TX 78957-0389, USA.
Mol Carcinog. 2005 Oct;44(2):122-36. doi: 10.1002/mc.20127.
Previous data from two-stage carcinogenesis studies in mouse skin demonstrated that genetic control of susceptibility to skin tumor promotion by the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), in crosses between susceptible DBA/2J and resistant C57BL/6J mice is a multigenic trait. Utilizing a cDNA microarray approach, we compared global gene expression profiles in the epidermis of these two mouse strains treated with TPA or vehicle (acetone). Gene expression in the epidermis was analyzed after the treatment to identify global effects of TPA, as well as potential candidate genes that modify susceptibility to skin tumor promotion. DBA/2J and C57BL/6J mice were treated topically four times with 3.4 nmol TPA or acetone over a 2-wk period, and RNA was extracted from epidermis 6 h after the final treatment. Labeled cDNA generated from each group was hybridized to commercial cDNA microarrays (Agilent) containing more than 8000 targets. More than 450 genes were significantly influenced, directly or indirectly, by TPA treatment in the epidermis of either strain. Notably, 44 genes exhibited differential expression between the tumor promotion sensitive and resistant mouse strains. Several genes that were differentially expressed in DBA/2J versus C57BL/6J epidermis after TPA treatment were located in chromosomal regions linked to TPA promotion susceptibility. Three genes, Gsta4, Nmes1 (MGC58382), and Serpinb2, located within promotion susceptibility loci Psl1 (chr 9), Psl2 (chr 2), and Psl3 (chr 1), respectively, were identified in this analysis as potential candidates for modifiers of susceptibility to skin tumor promotion by TPA.
先前在小鼠皮肤进行的两阶段致癌研究数据表明，在易感性DBA/2J小鼠和抗性C57BL/6J小鼠的杂交实验中，佛波酯12 - O - 十四烷酰佛波醇 - 13 - 乙酸酯（TPA）对皮肤肿瘤促进易感性的遗传控制是一种多基因性状。利用cDNA微阵列方法，我们比较了用TPA或赋形剂（丙酮）处理的这两种小鼠品系表皮中的全局基因表达谱。处理后分析表皮中的基因表达，以确定TPA的全局效应以及修饰皮肤肿瘤促进易感性的潜在候选基因。在2周内，用3.4 nmol TPA或丙酮对DBA/2J和C57BL/6J小鼠进行4次局部处理，在最后一次处理后6小时从表皮提取RNA。每组产生的标记cDNA与包含8000多个靶点的商业cDNA微阵列（安捷伦）杂交。在任一品系的表皮中，超过450个基因受到TPA处理的直接或间接显著影响。值得注意的是，44个基因在肿瘤促进敏感和抗性小鼠品系之间表现出差异表达。TPA处理后，在DBA/2J与C57BL/6J表皮中差异表达的几个基因位于与TPA促进易感性相关联的染色体区域。在该分析中，分别位于促进易感性位点Psl1（9号染色体）、Psl2（2号染色体）和Psl（1号染色体）内的三个基因Gsta4、Nmes1（MGC58382）和Serpinb2被确定为TPA诱导皮肤肿瘤促进易感性修饰因子的潜在候选基因。
