Wong Chris K M, Lai Teresa, Holly Jeffrey M P, Wheeler Malcolm H, Stewart Claire E H, Farndon John R
Division of Surgery, University of Bristol, Bristol Royal Infirmary, Marlborough Street, Bristol, United Kingdom, BS2 8HW.
World J Surg. 2006 May;30(5):714-20. doi: 10.1007/s00268-005-0340-2.
The importance of the IGF system in HPT has been previously demonstrated. Additionally, the role of vitamin A in HPT has been reported. Retinoic acid (RA), a derivative of vitamin A, is a ligand for the IGF II receptor (IGF2R). We have evaluated the interactions of RA with the IGF system in a primary parathyroid cell culture model.
Primary cell cultures were prepared from nine patients. Following adhesion, the cells were transferred to serum-free medium and dosed once with growth factors +/- RA for 96 hours. Proliferation was assessed by measuring tritiated thymidine incorporation.
Compared with the control group (100%), both IGF I and II increased DNA synthesis significantly. Retinoic acid significantly reduced the basal DNA synthesis to 82.2% +/- 4.2% compared with control (P < 0.05). Retinoic acid x10(-5) M completely abrogated the proliferative actions of IGF II (70.2% +/- 9.7%, P < 0.05) but had no significant effect on the IGF I response (P > 0.05). To evaluate the role of IGF2R or IGFBPs in mediating the actions of RA, the IGF II analogs [Leu27]IGF II (10-20-fold reduced IGF I receptor affinity) and des(1-6) IGF II (lower IGFBP binding affinity) were used. The IGF II inhibitory effect of RA was enhanced in the presence of analogs [Leu27]IGF II (P = 0.052) but not with des(1-6)IGF II (P > 0.05), compared with wild-type IGF II.
These data implicate a novel antiproliferative role for RA in enhancing the pericellular clearance of IGF II via the IGF2R preventing ligand activation of the IGF I receptor. This may have broader implications for RA effects in other tumors.
胰岛素样生长因子（IGF）系统在甲状旁腺功能亢进症（HPT）中的重要性此前已得到证实。此外，维生素A在HPT中的作用也有报道。视黄酸（RA）是维生素A的衍生物，是IGF II受体（IGF2R）的配体。我们在原代甲状旁腺细胞培养模型中评估了RA与IGF系统的相互作用。
从9名患者制备原代细胞培养物。细胞贴壁后，转移至无血清培养基中，用生长因子±RA处理一次，持续96小时。通过测量氚标记胸腺嘧啶核苷掺入量评估细胞增殖。
与对照组（100%）相比，IGF I和II均显著增加DNA合成。与对照组相比，视黄酸显著降低基础DNA合成至82.2%±4.2%（P<0.05）。视黄酸10⁻⁵ M完全消除了IGF II的增殖作用（70.2%±9.7%，P<0.05），但对IGF I反应无显著影响（P>0.05）。为评估IGF2R或胰岛素样生长因子结合蛋白（IGFBPs）在介导RA作用中的作用，使用了IGF II类似物[Leu27]IGF II（IGF I受体亲和力降低10 - 20倍）和des(1 - 6)IGF II（IGFBP结合亲和力较低）。与野生型IGF II相比，在存在类似物[Leu27]IGF II时，RA对IGF II的抑制作用增强（P = 0.052），而在存在des(1 - 6)IGF II时无增强（P>0.05）。
这些数据表明RA具有一种新的抗增殖作用，即通过IGF2R增强IGF II的细胞周清除，从而防止配体激活IGF I受体。这可能对RA在其他肿瘤中的作用具有更广泛的意义。
