Department of Neurosurgery and Laboratory of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, 730030, Gansu, China.
The Second Clinical Medical School, Lanzhou University, Lanzhou, 730030, Gansu, China.
Mol Neurobiol. 2024 Oct;61(10):7862-7876. doi: 10.1007/s12035-024-04036-4. Epub 2024 Mar 4.
Neurofibromatosis type 1 (NF1) is caused by NF1 gene mutations. Patients with NF1 often have complications with tumors, such as neurofibroma. In order to investigate the pathogenesis of human neurofibroma, a systematic comparison of protein expression levels between Schwann cell-like sNF96.2 cells, which originated from malignant peripheral nerve sheath tumors (MPNST), and normal Schwann cells was performed using 4-D label-free proteomic analysis. In addition, the expression levels and localization of dysregulated proteins were confirmed using a Gene Expression Omnibus (GEO) transcriptomic dataset, Western blot analysis, and immunofluorescence labeling. The effects of SRY-box transcription factor 9 (SOX9) in the neurofibroma and surrounding microenvironment were evaluated in vivo using a tumor transplantation model. The present study observed that SOX9 and procollagen C-endopeptidase enhancer (PCOLCE) were significantly altered. NF1 mutation promoted the nuclear translocation and transcriptional activity of SOX9 in neurofibromas. SOX9 increased collagen VI secretions by enhancing the activation of PCOLCE in neurofibroma cells. These findings might provide new perspectives on the pathophysiological significance of SOX9 in neurofibromas and elucidate a novel molecular mechanism underlying neurofibromas.
神经纤维瘤病 1 型（NF1）是由 NF1 基因突变引起的。NF1 患者常伴有肿瘤并发症，如神经纤维瘤。为了研究人类神经纤维瘤的发病机制，我们采用 4-D 无标记蛋白质组学分析，对源自恶性外周神经鞘瘤（MPNST）的 Schwann 细胞样 sNF96.2 细胞与正常 Schwann 细胞之间的蛋白质表达水平进行了系统比较。此外，我们使用基因表达综合数据库（GEO）转录组数据集、Western blot 分析和免疫荧光标记，对失调蛋白的表达水平和定位进行了确认。我们还通过肿瘤移植模型，评估了性别决定区 Y 框转录因子 9（SOX9）在神经纤维瘤及其周围微环境中的作用。本研究观察到 SOX9 和前胶原 C 内肽酶增强子（PCOLCE）的表达水平显著改变。NF1 突变促进了神经纤维瘤中 SOX9 的核转位和转录活性。SOX9 通过增强神经纤维瘤细胞中 PCOLCE 的激活，增加了胶原 VI 的分泌。这些发现可能为 SOX9 在神经纤维瘤中的病理生理意义提供新的视角，并阐明神经纤维瘤的新分子机制。
