Breun Maria, Schwerdtfeger Alexandra, Martellotta Donato Daniel, Kessler Almuth F, Monoranu Camelia M, Matthies Cordula, Löhr Mario, Hagemann Carsten
Department of Neurosurgery, University Hospital Würzburg, D-97080 Würzburg, Germany.
Department of Neuropathology, Institute of Pathology, University of Würzburg, D-97080 Würzburg, Germany.
Oncol Lett. 2020 Mar;19(3):1856-1864. doi: 10.3892/ol.2020.11299. Epub 2020 Jan 14.
A disintegrin and metalloproteinase 9 (ADAM9) is a member of the transmembrane ADAM family. It is expressed in different types of solid cancer and promotes tumor invasiveness. To the best of our knowledge, the present study was the first to examine ADAM9 expression in vestibular schwannomas (VS) from patients with and without neurofibromatosis type 2 (NF2) and to associate the data with clinical parameters of the patients. The aim of the present study was to evaluate if ADAM9 could be used as prognostic marker or therapeutic target. ADAM9 mRNA and protein levels were measured in VS samples (n=60). A total of 30 of them were from patients with neurofibromatosis. Healthy peripheral nerves from autopsies (n=10) served as controls. ADAM9 mRNA levels were measured by PCR, and protein levels were determined by immunohistochemistry (IHC) and western blotting (WB). The Hannover Classification was used to categorize tumor extension and hearing loss. ADAM9 mRNA levels were 8.8-fold higher in VS compared with in controls. The levels were 5.6-fold higher in patients with NF2 and 12-fold higher in patients with sporadic VS. WB revealed two mature isoforms of the protein, and according to IHC ADAM9 was mainly expressed by S100-positive Schwann cells. There was a strong correlation between ADAM9 mRNA expression and the level of functional impairment (r~1, p=0.01). Particularly, the secreted isoform of ADAM9 was expressed in patients with higher hearing impairment. ADAM9 mRNA was overexpressed in the tumor samples relative to healthy vestibular nerves, and there was an association between higher ADAM9 expression levels and greater hearing impairment. Therefore, ADAM9 may be a prognostic marker for VS, and ADAM9 inhibition might have the potential as a systemic approach for the treatment of VS.
解整合素金属蛋白酶9（ADAM9）是跨膜ADAM家族的成员。它在不同类型的实体癌中表达，并促进肿瘤侵袭。据我们所知，本研究首次检测了2型神经纤维瘤病（NF2）患者和非NF2患者的前庭神经鞘瘤（VS）中ADAM9的表达，并将数据与患者的临床参数相关联。本研究的目的是评估ADAM9是否可作为预后标志物或治疗靶点。在VS样本（n = 60）中测量ADAM9 mRNA和蛋白水平。其中30例来自神经纤维瘤病患者。尸检获得的健康周围神经（n = 10）用作对照。通过PCR测量ADAM9 mRNA水平，通过免疫组织化学（IHC）和蛋白质印迹（WB）测定蛋白水平。采用汉诺威分类法对肿瘤扩展和听力损失进行分类。VS中ADAM9 mRNA水平比对照高8.8倍。NF2患者中的水平高5.6倍，散发性VS患者中高12倍。WB显示该蛋白有两种成熟异构体，根据IHC，ADAM9主要由S100阳性雪旺细胞表达。ADAM9 mRNA表达与功能损害水平之间存在强相关性（r~1，p = 0.01）。特别是，ADAM9的分泌异构体在听力损害较高的患者中表达。相对于健康的前庭神经，肿瘤样本中ADAM9 mRNA过表达，并且ADAM9表达水平较高与更严重的听力损害之间存在关联。因此，ADAM9可能是VS的预后标志物，抑制ADAM9可能有作为VS全身治疗方法的潜力。
