Bufalieri Francesca, Caimano Miriam, Lospinoso Severini Ludovica, Basili Irene, Paglia Francesco, Sampirisi Luigi, Loricchio Elena, Petroni Marialaura, Canettieri Gianluca, Santoro Antonio, D'Angelo Luca, Infante Paola, Di Marcotullio Lucia
Department of Molecular Medicine, Sapienza University, Viale Regina Elena 291, 00161 Rome, Italy.
Dipartimento di Neurologia e Psichiatria, Neurochirurgia, Sapienza University, Viale dell'Università 30, 00185 Rome, Italy.
Cancers (Basel). 2020 Jan 30;12(2):321. doi: 10.3390/cancers12020321.
Glioblastoma multiforme (GB) is the most malignant primary brain tumor in humans, with an overall survival of approximatively 15 months. The molecular heterogeneity of GB, as well as its rapid progression, invasiveness and the occurrence of drug-resistant cancer stem cells, limits the efficacy of the current treatments. In order to develop an innovative therapeutic strategy, it is mandatory to identify and characterize new molecular players responsible for the GB malignant phenotype. In this study, the RNA-binding ubiquitin ligase MEX3A was selected from a gene expression analysis performed on publicly available datasets, to assess its biological and still-unknown activity in GB tumorigenesis. We find that MEX3A is strongly up-regulated in GB specimens, and this correlates with very low protein levels of RIG-I, a tumor suppressor involved in differentiation, apoptosis and innate immune response. We demonstrate that MEX3A binds RIG-I and induces its ubiquitylation and proteasome-dependent degradation. Further, the genetic depletion of MEX3A leads to an increase of RIG-I protein levels and results in the suppression of GB cell growth. Our findings unveil a novel molecular mechanism involved in GB tumorigenesis and suggest MEX3A and RIG-I as promising therapeutic targets in GB.
多形性胶质母细胞瘤（GB）是人类最恶性的原发性脑肿瘤，总体生存期约为15个月。GB的分子异质性，以及其快速进展、侵袭性和耐药性癌症干细胞的出现，限制了当前治疗的疗效。为了开发一种创新的治疗策略，必须识别和表征导致GB恶性表型的新分子参与者。在本研究中，从公开可用数据集中进行的基因表达分析中选择了RNA结合泛素连接酶MEX3A，以评估其在GB肿瘤发生中的生物学活性和仍未知的活性。我们发现MEX3A在GB标本中强烈上调，这与RIG-I的极低蛋白水平相关，RIG-I是一种参与分化、凋亡和先天免疫反应的肿瘤抑制因子。我们证明MEX3A结合RIG-I并诱导其泛素化和蛋白酶体依赖性降解。此外，MEX3A的基因缺失导致RIG-I蛋白水平增加，并导致GB细胞生长受到抑制。我们的研究结果揭示了一种参与GB肿瘤发生的新分子机制，并表明MEX3A和RIG-I是GB中有前景的治疗靶点。
