雌激素对Ⅰ型神经纤维瘤病发生机制的调控作用

Effects of estrogen on pathogenesis of neurofibromatosis type 1

目的探讨17β-雌二醇(E2)和E2受体拮抗剂对Ⅰ型神经纤维瘤病(NF1)神经纤维瘤的形成和发展的影响。方法3H-TdR掺入法研究E2对施万细胞增殖能力的影响;免疫印迹(Western-blot)方法检测E2及E2受体拮抗剂Tamoxifen对NF1患者神经纤维瘤中施万细胞NF1蛋白和hTERT蛋白表达的影响。结果随着E2孵育浓度和时间的增加,CPMA值有逐渐增加的趋势,其中10-7mol/L和10-6mol/L浓度作用24(分别为224.33±25.59和242.17±21.98)和48h(分别为234.83±28.15和257.83±28.86),CPMA值增高与对照组(154.33±17.89)相比差异有统计学意义,相同E2浓度孵育24和48h相比,CPMA值的差异没有统计学意义;E2处理组与对照组比较,E2+E2受体拮抗剂Tamoxifen处理组与E2处理组比较,NF1蛋白的表达差异皆无统计学意义;E2受体拮抗剂Tamoxifen处理组与对照组比较,NF1蛋白的表达差异无统计学意义;E2处理组与对照组比较,hTERT蛋白表达增高约3.31倍,差异有统计学意义;E2+E2受体拮抗剂Tamoxifen处理组与E2处理组相比,hTERT蛋白表达约降低39%,差异有统计学意义;E2受体拮抗剂Tamoxifen处理组与对照组相比,hTERT蛋白的表达差异无统计学意义。结论E2能够促进NF1神经纤维瘤中施万细胞的增殖;E2对NF1中神经纤维瘤形成的促进作用是通过提高hTERT蛋白表达,进而增加端粒酶活性促进细胞增殖这一通路实现的,而非上调NF1蛋白表达。E2的这一作用可以被E2受体拮抗剂Tamoxifen抑制。

Objective To explore the effects of 17β-estradiol （E2 ） and E2 receptor antagonist on the formation and development of neurofibromas in patients with neurofibromatosis type 1 （ NF1 ）. Methods The effect of E2 on the proliferation of Schwann cells by using 3^ H-thymidine incorporation and the effects of E2 and E2 receptor antagonist on expression of NF1 and hTERT protein in neurofibroma Schwann cells from patients with NF1 were detected by Western-blotting. Results The CPMA value of the Schwann cells was increased along with the increase of the incubating time and the concentration of E2. Compared with the control group, the CPMA values of Schwann cells incubated in E2 at the concentrations of 10-7 mol/L and 10 -6 mol/L for 24 （ 224.33 ± 25.59 and 242.17 ± 21.98 respectively） and 48 hours （ 234.83 ± 28.15 and 257.83 ± 28.86） were increased significantly （ 154.33 ± 17.89 in control group）. When Schwann cells were incubated in the same concentrations for 24 and 48 hours, the difference between CPMA values was not remarkably significant. The differences of NF1 protein expression level between E2 treatment group and control group, between E2 and E2 receptor antagonist treatment groups and between E2 receptor antagonist treatment group and the control group was not remarkably significant. However, the hTERT protein expression level in E2 treatment group was 3.31 times higher than that in control group, and the difference was remarkably significant, meanwhile, the effect of E2 on the hTERT protein expression level can be decreased by 39% by E2 receptor antagonist. The difference in hTERT protein expression level between E： receptor antagonist treatment group and the control group was not remarkably significant. Conclusion E2 promotes the proliferation of neurofibroma Schwann cells in patients with NF1 by increasing the expression of hTERT protein and in turn activates the telomerase, not by effecting the expression of NF1 protein though. The effect of E2 might be inhibited by tamoxifen.