Atallah Isis, Cieza Rivera Ana M, Rivero Lezcano Octavio M, Tascón-González Laura, González-Cortés Carolina, Diez Tascón Cristina, Fernández-Villa Tania, Martín Vicente
Division of Genetic Medicine, Lausanne University Hospital 1011 Lausanne, Switzerland.
Faculty of Health Sciences, Department of Biomedical Sciences, Area of Preventive Medicine and Public Health, Universidad de León León 24071, Spain.
Am J Transl Res. 2022 May 15;14(5):3180-3188. eCollection 2022.
Neurofibromatosis type 1 (NF1) predisposes to the development of dermal and plexiform neurofibromas and serum of NF1 patients stimulates neurofibroma proliferation in vitro. This study aimed to determine whether, in NF1 patients, serum levels of midkine (MK) and fibroblast growth factor 2 (FGF2) were associated with the number and/or type of neurofibromas. In addition, their concentrations were correlated with serum levels of dehydroepiandrosterone sulfate (DHEAS), a neurosteroid secreted by the peripheral nervous system. We performed a case control-study and measured, by ELISA assay, serum concentrations of MK, FGF2, and DHEAS in 20 NF1 patients and 30 controls. We found increased serum levels of MK and FGF2 in NF1 patients between 30 and 50 years old. Their concentrations were significantly higher in NF1 patients with plexiform neurofibromas than in controls (P=0.003 for MK and P=0.008 for FGF2). As an underlying hormonal regulation was suspected, DHEAS serum levels were measured but no difference was observed between patients and controls. We also observed a strong association between MK and FGF2 levels (P=0.0001) in NF1 patients and controls. In conclusion, we point out MK and FGF2 as biomarkers for plexiform neurofibroma in NF1 patients. As both growth factors are estrogen-responsive genes and neurofibromin is a co-repressor of estrogen receptor alpha activity, we suggest that the increased serum levels of MK and FGF2 observed in NF1 patients might be due to estradiol hypersensitivity.
1型神经纤维瘤病（NF1）易引发皮肤和丛状神经纤维瘤，且NF1患者的血清在体外可刺激神经纤维瘤增殖。本研究旨在确定在NF1患者中，中期因子（MK）和碱性成纤维细胞生长因子2（FGF2）的血清水平是否与神经纤维瘤的数量和/或类型相关。此外，还将它们的浓度与硫酸脱氢表雄酮（DHEAS，一种由外周神经系统分泌的神经甾体）的血清水平进行了关联分析。我们开展了一项病例对照研究，通过酶联免疫吸附测定法（ELISA）检测了20例NF1患者和30例对照者血清中MK、FGF2和DHEAS的浓度。我们发现30至50岁的NF1患者血清中MK和FGF2水平升高。丛状神经纤维瘤患者的MK和FGF2浓度显著高于对照组（MK为P = 0.003，FGF2为P = 0.008）。由于怀疑存在潜在的激素调节作用，我们检测了DHEAS血清水平，但患者与对照组之间未观察到差异。我们还观察到NF1患者和对照者中MK与FGF2水平之间存在强关联（P = 0.0001）。总之，我们指出MK和FGF2是NF1患者丛状神经纤维瘤的生物标志物。由于这两种生长因子都是雌激素反应性基因，且神经纤维瘤蛋白是雌激素受体α活性的共抑制因子，我们认为NF1患者中观察到的MK和FGF2血清水平升高可能是由于雌二醇超敏反应所致。
