Laboratory of Cytogenomics and Environmental Mutagenesis, Environment Section (SAMAM), Evandro Chagas Institute (IEC), Ananindeua, Brazil.
Translational Immuno-Oncology Group, International Research Center, A.C. Camargo Cancer Center, São Paulo, Brazil.
Sci Rep. 2022 Apr 19;12(1):6442. doi: 10.1038/s41598-022-10114-1.
Gliomas are the most commonly occurring malignant brain tumor characterized by an immunosuppressive microenvironment accompanied by profound epigenetic changes, thus influencing the prognosis. Glutathione peroxidase 7 (GPX7) is essential for regulating reactive oxygen species homeostasis under oxidative stress. However, little is known about the function of GPX7 in gliomas. In this study, we hypothesized that GPX7 methylation status could influence biological functions and local immune responses that ultimately impact prognosis in adult gliomas. We conducted an integrated bioinformatics analysis mining GPX7 DNA methylation status, transcriptional and survival data of glioma patients. We discovered that GPX7 was remarkably increased in glioma tissues and cell lines, and was associated with poor prognosis. This upregulation was significantly linked to clinicopathological and molecular features, besides being expressed in a cell cycle-dependent manner. Our results consistently demonstrated that upregulation of GPX7 is tightly modulated by epigenetic processes, which also impacted the overall survival of patients with low-grade gliomas (LGG). Based on the analysis of biological functions, we found that GPX7 might be involved in immune mechanisms involving both innate and adaptive immunity, type I interferon production and regulation of synaptic transmission in LGG, whereas in GBM, it is mainly related to metabolic regulation of mitochondrial dynamics. We also found that GPX7 strongly correlates with immune cell infiltration and diverse immune cell markers, suggesting its role in tumor-specific immune response and in regulating the migration of immune cell types to the tumor microenvironment. Combining these multiple data, we provided the first evidence regarding the epigenetic-mediated regulatory mechanisms underlying GPX7 activation in gliomas. Furthermore, our study brings key insights into the significant effect of GPX7 in modulating both immune molecules and in immune cell infiltration in the microenvironment of gliomas, which might impact the patient outcome, opening up future opportunities to regulate the local immune response.
神经胶质瘤是最常见的恶性脑肿瘤，其特征为免疫抑制微环境，并伴有深刻的表观遗传改变，从而影响预后。谷胱甘肽过氧化物酶 7（GPX7）在氧化应激下对于调节活性氧稳态至关重要。然而，GPX7 在神经胶质瘤中的功能知之甚少。在这项研究中，我们假设 GPX7 的甲基化状态可能会影响生物学功能和局部免疫反应，最终影响成人神经胶质瘤的预后。我们进行了一项综合的生物信息学分析，挖掘了神经胶质瘤患者的 GPX7 DNA 甲基化状态、转录和生存数据。我们发现 GPX7 在神经胶质瘤组织和细胞系中显著增加，并且与不良预后相关。这种上调与临床病理和分子特征显著相关，并且以细胞周期依赖性方式表达。我们的结果一致表明，GPX7 的上调受到表观遗传过程的紧密调节，这也影响了低级别神经胶质瘤（LGG）患者的总生存率。基于对生物学功能的分析，我们发现 GPX7 可能参与涉及固有和适应性免疫、I 型干扰素产生和 LGG 突触传递调节的免疫机制，而在 GBM 中，它主要与线粒体动力学的代谢调节有关。我们还发现 GPX7 与免疫细胞浸润和多种免疫细胞标志物强烈相关，表明其在肿瘤特异性免疫反应和调节免疫细胞类型向肿瘤微环境迁移中的作用。结合这些多种数据，我们提供了关于 GPX7 在神经胶质瘤中激活的表观遗传介导调节机制的第一个证据。此外，我们的研究深入了解了 GPX7 调节免疫分子和免疫细胞浸润神经胶质瘤微环境的重要作用，这可能影响患者的预后，为调节局部免疫反应提供了未来的机会。
