Wang Jianghua, Yu Wendong, Cai Yi, Ren Chengxi, Ittmann Michael M
Department of Pathology, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX 77030, USA.
Neoplasia. 2008 Aug;10(8):847-56. doi: 10.1593/neo.08450.
Fibroblast growth factor receptor 4 (FGFR-4) is expressed at significant levels in almost all human prostate cancers, and expression of its ligands is ubiquitous. A common polymorphism of FGFR-4 in which arginine (Arg(388)) replaces glycine (Gly(388)) at amino acid 388 is associated with progression in human prostate cancer. We show that the FGFR-4 Arg(388) polymorphism, which is present in most prostate cancer patients, results in increased receptor stability and sustained receptor activation. In patients bearing the FGFR-4 Gly(388) variant, expression of Huntingtin-interacting protein 1 (HIP1), which occurs in more than half of human prostate cancers, also results in FGFR-4 stabilization. This is associated with enhanced proliferation and anchorage-independent growth in vitro. Our findings indicate that increased receptor stability and sustained FGFR-4 signaling occur in most human prostate cancers due to either the presence of a common genetic polymorphism or the expression of a protein that stabilizes FGFR-4. Both of these alterations are associated with clinical progression in patients with prostate cancer. Thus, FGFR-4 signaling and receptor turnover are important potential therapeutic targets in prostate cancer.
成纤维细胞生长因子受体4（FGFR - 4）在几乎所有人类前列腺癌中均有显著表达，其配体的表达也很普遍。FGFR - 4存在一种常见的多态性，即第388位氨基酸处精氨酸（Arg(388)）取代甘氨酸（Gly(388)），这与人类前列腺癌的进展相关。我们发现，大多数前列腺癌患者所具有的FGFR - 4 Arg(388)多态性会导致受体稳定性增加和受体持续激活。在携带FGFR - 4 Gly(388)变体的患者中，半数以上人类前列腺癌中出现的亨廷顿相互作用蛋白1（HIP1）的表达也会导致FGFR - 4稳定。这与体外增殖增强和不依赖贴壁生长有关。我们的研究结果表明，由于常见基因多态性的存在或稳定FGFR - 4的蛋白质的表达，大多数人类前列腺癌中会出现受体稳定性增加和FGFR - 4信号持续存在的情况。这两种改变均与前列腺癌患者的临床进展相关。因此，FGFR - 4信号传导和受体周转是前列腺癌重要的潜在治疗靶点。
