Kuhn Elisabetta, Natacci Federica, Corbo Massimo, Pisani Luigi, Ferrero Stefano, Bulfamante Gaetano, Gambini Donatella
Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy.
Pathology Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.
Antioxidants (Basel). 2023 Aug 4;12(8):1557. doi: 10.3390/antiox12081557.
The neurofibromatosis-1 gene () was initially characterized because its germline mutation is responsible for an inherited syndromic disease predisposing tumor development, in particular neurofibromas but also various malignancies. Recently, large-scale tumor sequencing efforts have demonstrated as one of the most frequently mutated genes in human cancer, being mutated in approximately 5-10% of all tumors, especially in malignant peripheral nerve sheath tumors and different skin tumors. acts as a tumor suppressor gene that encodes neurofibromin, a large protein that controls neoplastic transformation through several molecular mechanisms. On the other hand, neurofibromin loss due to biallelic inactivation induces tumorigenic hyperactivation of Ras and mTOR signaling pathways. Moreover, neurofibromin controls actin cytoskeleton structure and the metaphase-anaphase transition. Consequently, neurofibromin deficiency favors cell mobility and proliferation as well as chromosomal instability and aneuploidy, respectively. Growing evidence supports the role of oxidative stress in -related tumorigenesis. Neurofibromin loss induces oxidative stress both directly and through Ras and mTOR signaling activation. Notably, innovative therapeutic approaches explore drug combinations that further increase reactive oxygen species to boost the oxidative unbalance of -altered cancer cells. In our paper, we review -related tumors and their pathogenesis, highlighting the twofold contribution of oxidative stress, both tumorigenic and therapeutic.
神经纤维瘤病1基因（）最初被鉴定出来，是因为其种系突变会导致一种遗传性综合征疾病，易引发肿瘤，尤其是神经纤维瘤，也包括各种恶性肿瘤。最近，大规模肿瘤测序研究表明，该基因是人类癌症中最常发生突变的基因之一，在所有肿瘤中约有5%-10%发生突变，尤其是在恶性外周神经鞘瘤和不同类型的皮肤肿瘤中。该基因作为一种肿瘤抑制基因，编码神经纤维瘤蛋白，这是一种通过多种分子机制控制肿瘤转化的大型蛋白质。另一方面，由于双等位基因失活导致的神经纤维瘤蛋白缺失会诱导Ras和mTOR信号通路的致癌性过度激活。此外，神经纤维瘤蛋白控制肌动蛋白细胞骨架结构以及中期-后期转变。因此，神经纤维瘤蛋白缺乏分别有利于细胞迁移和增殖以及染色体不稳定和非整倍体。越来越多的证据支持氧化应激在与该基因相关的肿瘤发生中的作用。神经纤维瘤蛋白缺失直接或通过Ras和mTOR信号激活诱导氧化应激。值得注意的是，创新的治疗方法探索了药物组合，这些组合可进一步增加活性氧，以加剧与该基因改变的癌细胞的氧化失衡。在我们的论文中，我们综述了与该基因相关的肿瘤及其发病机制，强调了氧化应激在肿瘤发生和治疗方面的双重作用。
