Machado Gabriel Cardoso, Ferrer Valéria Pereira
Graduate Program in Pathological Anatomy, Faculty of Medicine, Rio de Janeiro Federal University, Rio de Janeiro, Brazil; Laboratory of Cell and Molecular Biology of Tumors, Department of Cell and Molecular Biology, Biology Institute, Fluminense Federal University, Niterói, Rio de Janeiro, Brazil.
Graduate Program in Pathological Anatomy, Faculty of Medicine, Rio de Janeiro Federal University, Rio de Janeiro, Brazil; Laboratory of Cell and Molecular Biology of Tumors, Department of Cell and Molecular Biology, Biology Institute, Fluminense Federal University, Niterói, Rio de Janeiro, Brazil.
Comput Biol Med. 2025 Mar;187:109730. doi: 10.1016/j.compbiomed.2025.109730. Epub 2025 Jan 31.
Adult-type diffuse gliomas arise from glial or progenitor cells. These tumors are currently classified as astrocytoma isocitrate dehydrogenase (IDH)-mutant or IDH-mutant oligodendroglioma with co-deletion of chromosomal arms 1p and 19q, both of which could be either slow-growing tumors, or glioblastoma (GBM), which is a more aggressive tumor. Despite advances in diagnosis and treatment, the median survival time after GBM diagnosis remains low at approximately 15 months, with a 5-year overall survival (OS) rate of 6.8 %. Therefore, new biomarker and therapeutic target discoveries are required to improve prognosis. Mucin 1 (MUC1) and MUC4 are membrane-bound mucins and potential biomarkers of several tumors. However, the role of these mucins in adult gliomas has not been well explored. In this retrospective study, in silico analysis of data from patients with adult-type diffuse glioma revealed differential methylation and expression patterns of MUC1 and MUC4 between GBM and non-GBM groups. In the GBM group, decreased methylation and elevated expression of MUC1 were observed (r = -0.25, p < 0.0001), whereas increased methylation and decreased expression of MUC4 were observed (r = -0.13, p = 0.1344). Conversely, in the non-GBM group, MUC1 exhibited higher methylation and lower expression (r = -0.27, p < 0.0001), whereas MUC4 showed lower methylation and higher expression (r = -0.32, p < 0.0001). The expression of these genes influenced OS in adult patients with glioma (p = 0.0344), with high MUC1 and low MUC4 expression associated with worse OS. MUC1 and MUC4 expression correlated with that of MUC20 in both GBM (r = 0.54) and non-GBM (r = 0.53) groups (p < 0.0001). Functional enrichment analysis identified the biological roles of MUC1-co-expressed genes as involvement in innate immunity, antigen processing, and proinflammatory responses in both the non-GBM and GBM groups, and integrin-based signaling pathways in the GBM group. MUC4-co-expressed genes are involved in ion transport in GBM patients. Using molecular docking, we observed that MUC1 domains physically interact with immune response-related proteins, such as receptors for advanced glycation end products (RAGE), major histocompatibility complex II (MHC-II), and extracellular matrix receptor integrin alpha 2 (ITGA2). To our knowledge, this is the first retrospective study and in silico analysis demonstrating the relevance and correlation of MUC1 and MUC4 in adult gliomas. These findings elucidate the molecular mechanisms underlying adult-type diffuse glioma progression and highlight MUC1 and MUC4 as potential prognostic markers and therapeutic targets for glioma management.
成人型弥漫性胶质瘤起源于神经胶质细胞或祖细胞。这些肿瘤目前被分类为异柠檬酸脱氢酶（IDH）突变型星形细胞瘤或伴有染色体臂1p和19q共同缺失的IDH突变型少突胶质细胞瘤，这两种肿瘤既可以是生长缓慢的肿瘤，也可以是胶质母细胞瘤（GBM），后者是一种侵袭性更强的肿瘤。尽管在诊断和治疗方面取得了进展，但GBM诊断后的中位生存时间仍然较低，约为15个月，5年总生存率（OS）为6.8%。因此，需要发现新的生物标志物和治疗靶点以改善预后。粘蛋白1（MUC1）和MUC4是膜结合粘蛋白，也是几种肿瘤的潜在生物标志物。然而，这些粘蛋白在成人胶质瘤中的作用尚未得到充分研究。在这项回顾性研究中，对成人型弥漫性胶质瘤患者的数据进行的计算机分析显示，GBM组和非GBM组之间MUC1和MUC4的甲基化和表达模式存在差异。在GBM组中，观察到MUC1甲基化降低和表达升高（r = -0.25，p < 0.0001），而MUC4甲基化增加和表达降低（r = -0.13，p = 0.1344）。相反，在非GBM组中，MUC1表现出较高的甲基化和较低的表达（r = -0.27，p < 0.0001），而MUC4表现出较低的甲基化和较高的表达（r = -0.32，p < 0.0001）。这些基因的表达影响成人胶质瘤患者的OS（p = 0.0344），MUC1高表达和MUC4低表达与较差的OS相关。在GBM组（r = 0.54）和非GBM组（r = 0.53）中，MUC1和MUC4的表达均与MUC20的表达相关（p < 0.0001）。功能富集分析确定，MUC1共表达基因在非GBM组和GBM组中的生物学作用涉及先天免疫、抗原加工和促炎反应，在GBM组中还涉及基于整合素信号通路。MUC4共表达基因在GBM患者中参与离子转运。通过分子对接，我们观察到MUC1结构域与免疫反应相关蛋白发生物理相互作用，如晚期糖基化终产物受体（RAGE）、主要组织相容性复合体II（MHC-II）和细胞外基质受体整合素α2（ITGA2）。据我们所知，这是第一项证明MUC1和MUC4在成人胶质瘤中的相关性和关联性的回顾性研究及计算机分析。这些发现阐明了成人型弥漫性胶质瘤进展的分子机制，并突出了MUC1和MUC4作为胶质瘤管理的潜在预后标志物和治疗靶点。
