Yang Jingyi, Shen Lei, Zhou Jiabin, Wu Ji, Yue Chuqiao, Wang Tiansheng, Chai Songshan, Cai Yuankun, Xu Dongyuan, Lei Yu, Zhao Jingwei, Zhou Yixuan, Mei Zhimin, Xiong Nanxiang
Department of Neurosurgery, Zhongnan Hospital of Wuhan University, No.169, Donghu Road, Wuhan, 430071, Hubei, China.
Biochem Genet. 2024 Oct 2. doi: 10.1007/s10528-024-10928-w.
Lower-grade glioma (LGG) is a common primary brain tumor with a highly heterogeneous clinical presentation, and its prognosis cannot be accurately predicted by current histopathology. It has been found that mitochondria play an important role in hypoxia, angiogenesis, and energy metabolism in glioma, and mitochondrial function may have an important impact on LGG prognosis. The goal of this study was to develop a novel prognostic model based on Mitochondrial-related genes (MRGs). We first analyzed the somatic alterations profiles of MRGs in patients with LGG and found that somatic alterations were common in LGG and correlated with prognosis. Using RNA-seq data from TCGA and CGGA, 12 prognosis-related MRGs were identified to construct a mitochondrial activation score (MiAS) model by combining univariate regression and LASSO regression analysis. The model and nomogram were evaluated using the area under the ROC curve with AUC = 0.910. The model was closely correlated with the clinical characteristics of LGG patients and performed well in predicting the prognosis of LGG patients with significantly shorter overall survival (OS) time in the high-MiAS group. GSVA and GSEA results showed that oxidative stress, pro-cancer, and immune-related pathways were significantly enriched in the high-MiAS group. CIBERSORT results showed that MiAS was significantly associated with immune cell infiltration in LGG. Macrophage M1 and follicular helper T cells had increased infiltration in the high-MiAS group. TIDE predicted a better immunotherapy outcome in patients in the low-MiAS group. Finally, using data from the CTRPv2 and GDSC2 datasets to assess chemotherapy response in LGG, it was predicted that the chemotherapeutic agents AZD6482, MG-132, and PLX-4720 might be potential agents for patients in the high-MiAS group of LGG. In addition, we performed in vitro experiments and found that knockdown of OCIAD2 expression reduced the abilities of glioma cells to proliferate, migrate, and invade. In contrast, overexpression of OCIAD2 enhanced these abilities of glioma cells. This study found that MRGs were correlated with LGG patient prognosis, which is expected to provide new treatment strategies for LGG patients with different MiAS.
低级别胶质瘤（LGG）是一种常见的原发性脑肿瘤，临床表现高度异质性，目前的组织病理学无法准确预测其预后。研究发现，线粒体在胶质瘤的缺氧、血管生成和能量代谢中起重要作用，线粒体功能可能对LGG预后有重要影响。本研究的目的是基于线粒体相关基因（MRGs）开发一种新的预后模型。我们首先分析了LGG患者MRGs的体细胞改变谱，发现体细胞改变在LGG中很常见且与预后相关。利用来自TCGA和CGGA的RNA-seq数据，通过单变量回归和LASSO回归分析，鉴定出12个与预后相关的MRGs，构建了线粒体激活评分（MiAS）模型。使用ROC曲线下面积评估该模型和列线图，AUC = 0.910。该模型与LGG患者的临床特征密切相关，在预测高MiAS组总生存期（OS）时间显著缩短的LGG患者预后方面表现良好。GSVA和GSEA结果显示，高MiAS组氧化应激、促癌和免疫相关通路显著富集。CIBERSORT结果显示，MiAS与LGG中的免疫细胞浸润显著相关。高MiAS组巨噬细胞M1和滤泡辅助性T细胞浸润增加。TIDE预测低MiAS组患者免疫治疗效果更好。最后，利用CTRPv2和GDSC2数据集的数据评估LGG中的化疗反应，预测化疗药物AZD6482、MG-132和PLX-4720可能是LGG高MiAS组患者的潜在药物。此外，我们进行了体外实验，发现敲低OCIAD2表达可降低胶质瘤细胞的增殖、迁移和侵袭能力。相反，OCIAD2的过表达增强了胶质瘤细胞的这些能力。本研究发现MRGs与LGG患者预后相关，有望为不同MiAS的LGG患者提供新的治疗策略。
