Lefèvre Gaëlle, Babchia Narjes, Calipel Armelle, Mouriaux Frédéric, Faussat Anne-Marie, Mrzyk Stefanie, Mascarelli Frédéric
Cordeliers Research Center, Pierre et Marie Curie University, Paris France.
Invest Ophthalmol Vis Sci. 2009 Mar;50(3):1047-57. doi: 10.1167/iovs.08-2378. Epub 2008 Nov 21.
Constitutive activation of ERK1/2 controls proliferation of uveal melanoma cells. Because an autocrine fibroblast growth factor (FGF) activation loop controls ERK1/2 activation in many cancers, this study was conducted to examine the role of the FGF/FGF receptor autocrine loop in the ERK1/2-dependent proliferation and survival of uveal melanoma cells.
Primary tumors and cell lines (OCM-1, MKT-BR, SP6.5, Mel270 and 92.1) were used to define the role of the FGF/FGFR system in human uveal melanoma. Cell proliferation was assessed by MTT-staining, and apoptosis was quantified by flow cytometry. Specific pharmacologic inhibitors of ERK1/2 and FGFR1, an anti-FGF2 neutralizing antibody and an antisense oligonucleotide directed against FGF2 were used to analyze signaling in the FGF/FGFR autocrine loop.
FGF1, FGF2, and their FGFR1 receptor were strongly expressed in the primary uveal melanomas. All five uveal melanoma cell lines expressed and secreted FGF2. They also expressed FGFR1. Cell proliferation was strongly reduced by the antisense oligonucleotide-mediated depletion of endogenous FGF2, immunoneutralization of secreted FGF2, and pharmacologic inhibition of FGFR1. The FGF2/FGFR1-mediated signaling pathway was identified by showing that inhibition of either FGF2 or FGFR1 reduced ERK1/2 activation, cell proliferation, and survival.
The FGF/FGFR/ERK signaling pathway may be a target for therapeutic strategies against uveal melanoma.
ERK1/2的组成性激活控制葡萄膜黑色素瘤细胞的增殖。由于自分泌成纤维细胞生长因子（FGF）激活环在许多癌症中控制ERK1/2的激活，因此进行本研究以探讨FGF/FGF受体自分泌环在葡萄膜黑色素瘤细胞ERK1/2依赖性增殖和存活中的作用。
使用原发性肿瘤和细胞系（OCM-1、MKT-BR、SP6.5、Mel270和92.1）来确定FGF/FGFR系统在人葡萄膜黑色素瘤中的作用。通过MTT染色评估细胞增殖，通过流式细胞术对细胞凋亡进行定量分析。使用ERK1/2和FGFR1的特异性药理抑制剂、抗FGF2中和抗体以及针对FGF2的反义寡核苷酸来分析FGF/FGFR自分泌环中的信号传导。
FGF1、FGF2及其FGFR1受体在原发性葡萄膜黑色素瘤中强烈表达。所有五种葡萄膜黑色素瘤细胞系均表达并分泌FGF2。它们也表达FGFR1。反义寡核苷酸介导的内源性FGF2消耗、分泌型FGF2的免疫中和以及FGFR1的药理抑制均能显著降低细胞增殖。通过显示抑制FGF2或FGFR1均可降低ERK1/2激活、细胞增殖和存活，从而确定了FGF2/FGFR1介导的信号通路。
FGF/FGFR/ERK信号通路可能是葡萄膜黑色素瘤治疗策略的靶点。
