Developmentally-related candidate retinoic acid target genes regulated early during neuronal differentiation of human embryonal carcinoma
Developmentally-related candidate retinoic acid target genes regulated early during neuronal differentiation of human embryonal carcinoma
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DOI：
10.1038/sj.onc.1205408
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发表时间：
2002-04-25
期刊：
影响因子：
8
通讯作者：
Spinella, MJ
中科院分区：
文献类型：
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作者：
Freemantle, SJ;Kerley, JS;Spinella, MJ
胚胎癌是胚胎发育和肿瘤细胞分化的模型。为了响应全反式视黄酸 (RA)，人胚胎癌 (EC) 细胞系 NT2/D1 分化为神经元谱系，并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，我们试图确定 NT2/D1 细胞分化过程中 RA 的早期下游靶点。 RA总共诱导了57个基因，抑制了37个基因。 RA 调节基因在 8 小时时受到限制，其中 27 个基因被诱导，5 个基因被抑制。 RA反应转录本的总数在24和48小时时增加，并且它们的表达模式更加对称。对于给定的时间点，表达阵列上的 128 个 cDNA 中只有不到 1% 受到 RA 的调节。许多这些基因产物与发育途径相关，包括 TGF-β（Lefty A、NMA、卵泡抑素）、同源结构域（HoxD1、Meis2、Meis1、Gbx2）、IGF（IGFBP3、IGFBP6、CTGF）、Notch（躁狂边缘、ADAM 11）、Hedgehog（补丁）和 Wnt（Frat2，分泌型卷曲相关蛋白 1）发信号。此外，RA 在 2448 小时诱导的大量基因与细胞粘附、细胞骨架和基质重塑、生长抑制和细胞内信号级联相关。大多数被抑制的基因与蛋白质/RNA 加工、周转或代谢有关。鉴定出的早期诱导基因可能在 RA 介导的生长抑制和终末分化中发挥调节作用，并且在正常人类发育和基于类维生素A的癌症治疗或预防期间可能具有生理或药理学重要性。
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 micro-arrays 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 128 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, ADAM 11), Hedgehog (patched) and Wnt (Frat2, secreted frizzled-related protein 1) signaling. In addition a large cassette of genes induced by RA at 2448 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.