Ruohola J K, Valve E M, Vainikka S, Alitalo K, Härkönen P L
Department of Anatomy, and MediCity Research Laboratory, University of Turku, Finland.
Endocrinology. 1995 May;136(5):2179-88. doi: 10.1210/endo.136.5.7536664.
We studied the androgen regulation of fibroblast growth factor (FGF) receptors (FGFRs) in the Shionogi 115 (S115) mouse mammary tumor cell line and its genetic variant Clone 22. In S115 cells, androgen maintains a transformed morphology, rate of proliferation, and serum and anchorage independence. Similar effects were induced by treatment of the cells with FGF-2 or a heparin-binding growth factor (HBGF) fraction prepared from the medium conditioned by the cells. The effects of androgen and FGF-2 could be partly reversed with a specific anti-FGF-2 immunoglobulin G or by suramin, which inhibits binding of FGFs to their high affinity receptors. Testosterone and FGF-2 increased the expression of FGFR-1 messenger RNA (mRNA) and, to a lesser extent, FGFR-3 mRNA, but down-regulated FGFR-2 mRNA in S115 cells. No FGFR-4 mRNA was detected. FGF-2 also down-regulated the expression of syndecan-1, a heparan sulfate proteoglycan that binds FGF with low affinity. The binding of radiolabeled FGF-2 to FGFRs was lower in the cells cultured with testosterone or in the presence of the HBGFs from androgen-treated cells, presumably because of the autocrine production of FGF-like factors. In Clone 22 cells, FGFRs and syndecan-1 responded to androgen as in S115 cells, but they were less sensitive to FGF-2. Androgen or FGF-2 could not induce morphological transformation, although both stimulated proliferation. Androgen-increased proliferation was not, however, decreased by anti-FGF-2 immunoglobulin G in Clone 22 cells. These data suggest that of the HBGFs produced, FGF-2 is required in androgen induction of morphological change, whereas the effect on proliferation involves other factors as well (perhaps mostly FGF-8). The results show that androgen differentially regulates the expression of the high and low affinity FGF receptors, which could mediate androgen induction of the transformed phenotype in S115 cells by an autocrine mechanism. The differential responses of the Clone 22 variant cells to androgen and FGF-2 suggest that the pathways of steroid induction of different parameters of the transformed phenotype, such as transition to fibroblastic morphology and stimulation of proliferation, are divergent.
我们研究了雄激素对日本清澄115（S115）小鼠乳腺肿瘤细胞系及其基因变体克隆22中成纤维细胞生长因子（FGF）受体（FGFRs）的调控作用。在S115细胞中，雄激素维持着转化的形态、增殖速率以及血清非依赖性和锚定非依赖性。用FGF - 2或从细胞条件培养基中制备的肝素结合生长因子（HBGF）组分处理细胞，可诱导出类似的效应。雄激素和FGF - 2的效应可用特异性抗FGF - 2免疫球蛋白G或苏拉明部分逆转，苏拉明可抑制FGFs与其高亲和力受体的结合。睾酮和FGF - 2增加了FGFR - 1信使核糖核酸（mRNA）的表达，在较小程度上也增加了FGFR - 3 mRNA的表达，但下调了S115细胞中FGFR - 2 mRNA的表达。未检测到FGFR - 4 mRNA。FGF - 2还下调了syndecan - 1的表达，syndecan - 1是一种以低亲和力结合FGF的硫酸乙酰肝素蛋白聚糖。在用睾酮培养的细胞或存在来自雄激素处理细胞的HBGFs的情况下，放射性标记的FGF - 2与FGFRs的结合较低，这可能是由于FGF样因子的自分泌产生。在克隆22细胞中，FGFRs和syndecan - 1对雄激素的反应与S115细胞中相同，但它们对FGF - 2的敏感性较低。雄激素或FGF - 2不能诱导形态转化，尽管两者都刺激了增殖。然而，在克隆22细胞中，抗FGF - 2免疫球蛋白G并没有降低雄激素诱导的增殖。这些数据表明，在所产生的HBGFs中，FGF - 2是雄激素诱导形态变化所必需的，而对增殖的影响还涉及其他因素（可能主要是FGF - 8）。结果表明，雄激素差异性地调控高亲和力和低亲和力FGF受体的表达，这可能通过自分泌机制介导雄激素诱导S115细胞中的转化表型。克隆22变体细胞对雄激素和FGF - 2的不同反应表明，类固醇诱导转化表型不同参数（如向成纤维细胞形态的转变和增殖的刺激）的途径是不同的。
