Boyle B J, Harris V K, Liaudet-Coopman E D, Riegel A T, Wellstein A
Departments of Oncology and Pharmacology, Vincent T. Lombardi Cancer Center, Georgetown University, 20007, USA, Washington, DC, USA.
Biochem Pharmacol. 2000 Dec 1;60(11):1677-84. doi: 10.1016/s0006-2952(00)00507-4.
We have demonstrated earlier that a secreted fibroblast growth factor-binding protein (FGF-BP) can enhance angiogenesis and promote tumor growth in vivo. Furthermore, we found that FGF-BP expression in squamous cell carcinoma (SCC) is reduced by concentrations of retinoids that are effective in the treatment of SCC and that this repression can occur at the transcriptional and post-transcriptional level. To further examine the mechanism of regulation of FGF-BP by retinoids and the role played by retinoid receptor subtypes, we utilized retinoic acid receptor (RAR)-selective (TTNPB) and retinoid X receptor (RXR)-selective (LG100268) ligands. In ME-180 SCC cells, FGF-BP mRNA was down-regulated by TTNPB with an IC(50) value of 1 nM, whereas transcription was only repressed at 10,000-fold higher concentrations (IC(50) > 10 microM). This suggests that the major effects of retinoids on FGF-BP occur at the post-transcriptional level. In four additional SCC cell lines, FGF-BP was also down-regulated by TTNPB with IC(50) values of </= 1 nM, demonstrating that RAR receptors can modulate FGF-BP mRNA levels very effectively in SCC cells. The RXR-selective ligand on its own was only effective in two of the five cell lines (IC(50) of approximately 1 nM). In all of the SCC cell lines, a low concentration of RAR sensitized FGF-BP mRNA to treatment with the RXR ligand and the combination of the RXR and RAR ligands enhanced the efficacy beyond that of the individual ligands. We conclude that RAR receptors are major regulators of FGF-BP mRNA at the post-transcriptional level and propose that an RAR-induced gene product mediates the RXR effects on FGF-BP mRNA.
我们之前已经证明，一种分泌型成纤维细胞生长因子结合蛋白（FGF-BP）可增强血管生成并促进体内肿瘤生长。此外，我们发现，在鳞状细胞癌（SCC）中，FGF-BP的表达会被对SCC治疗有效的视黄酸浓度所降低，且这种抑制可发生在转录和转录后水平。为了进一步研究视黄酸对FGF-BP的调控机制以及视黄酸受体亚型所起的作用，我们使用了视黄酸受体（RAR）选择性（TTNPB）和视黄酸X受体（RXR）选择性（LG100268）配体。在ME-180 SCC细胞中，TTNPB可下调FGF-BP mRNA，IC（50）值为1 nM，而转录仅在高10000倍的浓度（IC（50）>10 μM）下才受到抑制。这表明视黄酸对FGF-BP的主要作用发生在转录后水平。在另外四种SCC细胞系中，FGF-BP也被TTNPB下调，IC（50）值≤1 nM，表明RAR受体可在SCC细胞中非常有效地调节FGF-BP mRNA水平。RXR选择性配体单独使用时仅在五个细胞系中的两个有效（IC（50）约为1 nM）。在所有SCC细胞系中，低浓度的RAR使FGF-BP mRNA对视黄酸X受体配体的处理敏感，且视黄酸X受体和视黄酸受体配体的组合增强了疗效，超过了单个配体的效果。我们得出结论，RAR受体是转录后水平上FGF-BP mRNA的主要调节因子，并提出一种RAR诱导的基因产物介导了视黄酸X受体对FGF-BP mRNA的影响。
