Acyclic retinoid inhibits human hepatoma cell growth by suppressing fibroblast growth factor-mediated signaling pathways
Acyclic retinoid inhibits human hepatoma cell growth by suppressing fibroblast growth factor-mediated signaling pathways
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DOI：
10.1053/j.gastro.2004.09.077
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发表时间：
2005-01-01
期刊：
影响因子：
29.4
通讯作者：
Omata, M
中科院分区：
文献类型：
--
作者：
Shao, RX;Otsuka, M;Omata, M
背景与目的：肝细胞癌（HCC）是人类最常见的恶性肿瘤之一。其高死亡率主要是高肝内复发的结果。新型合成类维生素A无环类维生素A（ACR）已被报道可预防原发性肝癌手术切除后的复发，但其作用的分子机制仍有待阐明。本研究阐明了ACR的分子靶点。方法：采用生长抑制法测定ACR对小鼠的生长抑制作用。通过报告基因分析对ACR诱导的细胞内信号传导进行了全面研究。使用微阵列检查ACR引起的基因表达变化。根据这些结果，确定了由ACR调节的候选信号传导途径，并检查了拮抗该途径是否逆转该作用。结果如下：我们发现，ACR通过下调成纤维细胞生长因子（FGF）受体3的表达和FGF介导的信号转导，进而抑制Rho和血清反应因子介导的转录活性，抑制肝癌细胞的生长。相反，FGF受体3的活性形式的过表达或FGF的添加逆转ACR介导的生长抑制。此外，通过RNA干扰沉默FGF受体3基因抑制细胞生长。结论：这些研究表明，ACR是FGF信号传导的有效抑制剂，选择性阻断FGF介导的通路可能是治疗HCC患者的一种有前途的治疗方法。
Background& Aims: Hepatocellular carcinoma (HCC) is one of the most common human malignancies. Its high mortality rate is mainly a result of high intrahepatic recurrence. The novel synthetic retinoid acyclic retinoid (ACR) has been reported to prevent the recurrence of human HCC after surgical resection of primary tumors, but the molecular mechanisms underlying its effects remain to be elucidated. In this study, we clarified the molecular targets of ACR. Methods: The inhibitory effects by ACR on growth were examined. Intracellular signaling induced by ACR was comprehensively studied by a reporter assay. Gene expression changes by ACR were examined using a microarray. From these results, a candidate signaling pathway modulated by ACR was determined and whether antagonizing this pathway reverses the effect was examined. Results: We show that ACR inhibits the growth of HCC cells through the down-regulation of fibroblast growth factor (FGF) receptor 3 expression and FGF-mediated signaling, which in turn suppresses the activity of Rho and serum response factor-mediated transcription. Conversely, overexpression of the active form of FGF receptor 3 or the addition of FGF reverses the ACR-mediated inhibition of growth. In addition, silencing the FGF receptor 3 gene by RNA interference inhibits cell growth. Conclusions: These studies show that ACR is a potent inhibitor of FGF signaling and that selective blocking of the FGFmediated pathway could be a promising therapeutic approach for the management of patients with HCC.