Freemantle Sarah J, Kerley Joanna S, Olsen Shannon L, Gross Robert H, Spinella Michael J
The Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire, NH 03755, USA.
Oncogene. 2002 Apr 25;21(18):2880-9. doi: 10.1038/sj.onc.1205408.
Embryonal carcinoma is a model of embryonic development as well as tumor cell differentiation. In response to all-trans retinoic acid (RA), the human embryonal carcinoma (EC) cell line, NT2/D1, differentiates toward a neuronal lineage with associated loss of cell growth and tumorigenicity. Through the use of cDNA-based microarrays we sought to identify the early downstream targets of RA during differentiation commitment of NT2/D1 cells. A total of 57 genes were induced and 37 genes repressed by RA. RA regulated genes were restricted at 8 h with 27 genes induced and five repressed. The total number of RA-responsive transcripts increased at 24 and 48 h and their pattern of expression was more symmetrical. For a given time point less than 1% of the 9128 cDNAs on the expression array were regulated by RA. Many of these gene products are associated with developmental pathways including those of TGF-beta (Lefty A, NMA, follistatin), homeo domain (HoxD1, Meis2, Meis1, Gbx2), IGF (IGFBP3, IGFBP6, CTGF), Notch (manic fringe, ADAM11), Hedgehog (patched) and Wnt (Frat2, secreted frizzled-related protein 1) signaling. In addition a large cassette of genes induced by RA at 24-48 h are associated with cell adhesion, cytoskeletal and matrix remodeling, growth suppression and intracellular signaling cascades. The majority of repressed genes are associated with protein/RNA processing, turnover or metabolism. The early induced genes identified may play a regulatory role in RA-mediated growth suppression and terminal differentiation and may have physiologic or pharmacologic importance during normal human development and retinoid-based cancer therapy or prevention.
胚胎癌是胚胎发育以及肿瘤细胞分化的一种模型。人胚胎癌细胞系NT2/D1在全反式维甲酸（RA）的作用下，向神经谱系分化，同时伴随着细胞生长和致瘤性的丧失。通过使用基于cDNA的微阵列，我们试图在NT2/D1细胞分化过程中鉴定RA的早期下游靶点。共有57个基因被RA诱导，37个基因被RA抑制。RA调控的基因在8小时时受到限制，有27个基因被诱导，5个基因被抑制。RA反应性转录本的总数在24小时和48小时增加，其表达模式更加对称。对于给定的时间点，表达阵列上9128个cDNA中不到1%受RA调控。这些基因产物中的许多与发育途径相关，包括转化生长因子-β（Lefty A、NMA、卵泡抑素）、同源结构域（HoxD1、Meis2、Meis1、Gbx2）、胰岛素样生长因子（IGFBP3、IGFBP6、结缔组织生长因子）、Notch（疯狂边缘蛋白、ADAM11）、Hedgehog（patched）和Wnt（Frat2、分泌型卷曲相关蛋白1）信号通路。此外，在24 - 48小时被RA诱导的一大组基因与细胞黏附、细胞骨架和基质重塑、生长抑制以及细胞内信号级联反应相关。大多数被抑制的基因与蛋白质/RNA加工、周转或代谢相关。所鉴定的早期诱导基因可能在RA介导的生长抑制和终末分化中起调节作用，并且在正常人类发育以及基于维甲酸的癌症治疗或预防过程中可能具有生理或药理重要性。
