Heim Kelly C, White Kristina A, Deng Dexin, Tomlinson Craig R, Moore Jason H, Freemantle Sarah J, Spinella Michael J
Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, USA.
Mol Cancer. 2007 Sep 19;6:57. doi: 10.1186/1476-4598-6-57.
The use of retinoids as anti-cancer agents has been limited due to resistance and low efficacy. The dynamics of nuclear receptor coregulation are incompletely understood. Cell-and context-specific activities of nuclear receptors may be in part due to distinct coregulator complexes recruited to distinct subsets of target genes. RIP140 (also called NRIP1) is a ligand-dependent corepressor that is inducible with retinoic acid (RA). We had previously shown that RIP140 limits RA induced tumor cell differentiation of embryonal carcinoma; the pluriopotent stem cells of testicular germ cell tumors. This implies that RIP140 represses key genes required for RA-mediated tumor cell differentiation. Identification of these genes would be of considerable interest.
To begin to address this issue, microarray technology was employed to elucidate in a de novo fashion the global role of RIP140 in RA target gene regulation of embryonal carcinoma. Subclasses of genes were affected by RIP140 in distinct manners.Interestingly, approximately half of the RA-dependent genes were unaffected by RIP140. Hence, RIP140 appears to discriminate between different classes of RA target genes. In general, RIP140-dependent gene expression was consistent with RIP140 functioning to limit RA signaling and tumor cell differentiation. Few if any genes were regulated in a manner to support a role for RIP140 in "active repression". We also demonstrated that RIP140 silencing sensitizes embryonal carcinoma cells to low doses of RA.
Together the data demonstrates that RIP140 has profound effects on RA-mediated gene expression in this cancer stem cell model. The RIP140-dependent RA target genes identified here may be particularly important in mediating RA-induced tumor cell differentiation and the findings suggest that RIP140 may be an attractive target to sensitize tumor cells to retinoid-based differentiation therapy. We discuss these data in the context of proposed models of RIP140-mediated repression.
由于耐药性和低疗效，类视黄醇作为抗癌药物的使用受到限制。核受体共调节的动态过程尚未完全了解。核受体的细胞和背景特异性活性可能部分归因于募集到不同靶基因亚群的不同共调节复合物。RIP140（也称为NRIP1）是一种依赖配体的共抑制因子，可被视黄酸（RA）诱导。我们之前已经表明，RIP140限制了RA诱导的胚胎癌细胞分化；睾丸生殖细胞肿瘤的多能干细胞。这意味着RIP140抑制了RA介导的肿瘤细胞分化所需的关键基因。鉴定这些基因将具有相当大的意义。
为了开始解决这个问题，采用微阵列技术以全新的方式阐明RIP140在胚胎癌RA靶基因调节中的整体作用。基因亚类受到RIP140的不同影响。有趣的是，大约一半的RA依赖基因不受RIP140影响。因此，RIP140似乎能够区分不同类别的RA靶基因。一般来说，RIP140依赖的基因表达与RIP140限制RA信号传导和肿瘤细胞分化的功能一致。几乎没有基因以支持RIP140在“主动抑制”中发挥作用的方式被调节。我们还证明，RIP140沉默使胚胎癌细胞对低剂量RA敏感。
这些数据共同表明，RIP140在这个癌症干细胞模型中对RA介导的基因表达有深远影响。这里鉴定出的RIP140依赖的RA靶基因在介导RA诱导的肿瘤细胞分化中可能特别重要，研究结果表明RIP140可能是使肿瘤细胞对基于类视黄醇的分化疗法敏感的有吸引力的靶点。我们在RIP140介导的抑制模型的背景下讨论这些数据。
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