Wu Haoneng, Zhao Qiuran, Ma Xiaobo, Zhao Ying, Wang Qing, Bai Jinguang, Huang Songling
Yunnan Key Laboratory of Laboratory Medicine, Kunming, Yunnan, China.
Yunnan Province Clinical Research Center for Laboratory Medicine, Kunming, Yunnan, China.
Biochem Genet. 2025 Apr 27. doi: 10.1007/s10528-025-11100-8.
Diffuse Large B-Cell Lymphoma (DLBCL) is an aggressive form of non-Hodgkin lymphoma with heterogeneous molecular characteristics. Altered metabolism, particularly mitochondrial function, has emerged as a critical factor in cancer progression. However, the role of mitochondrial metabolism in DLBCL remains poorly understood. This study aimed to identify key mitochondrial factors associated with DLBCL progression. We analyzed transcriptomic data from multiple DLBCL datasets (GSE83632, TCGA-GTEX, GSE181063, GSE4475) using differential expression analysis, weighted gene co-expression network analysis (WGCNA), and Gene Set Enrichment Analysis (GSEA). The expression and function of the identified key factor, Mitochondrial Pyruvate Carrier 2 (MPC2), were validated using clinical samples, DLBCL cell lines, and an in vivo mouse model of xenograft. Integrative bioinformatics analysis identified MPC2 as a significantly upregulated gene in DLBCL, associated with enrichment of oxidative phosphorylation (OXPHOS) and cell cycle-related genes. MPC2 overexpression was confirmed in clinical DLBCL samples and cell lines at both mRNA and protein levels. Knockdown of MPC2 in DLBCL cells impaired mitochondrial OXPHOS, increased glycolysis, and suppressed cell proliferation, invasion, and 3D spheroid formation. In vivo, MPC2 silencing significantly reduced tumor growth in a xenograft mouse model. Our findings reveal MPC2 as a key regulator of mitochondrial function in DLBCL, promoting tumor progression through enhanced OXPHOS. This study provides new insights into the metabolic reprogramming of DLBCL and suggests MPC2 as a potential therapeutic target for this aggressive lymphoma.
弥漫性大B细胞淋巴瘤（DLBCL）是一种具有异质性分子特征的侵袭性非霍奇金淋巴瘤。代谢改变，尤其是线粒体功能改变，已成为癌症进展的关键因素。然而，线粒体代谢在DLBCL中的作用仍知之甚少。本研究旨在确定与DLBCL进展相关的关键线粒体因子。我们使用差异表达分析、加权基因共表达网络分析（WGCNA）和基因集富集分析（GSEA），分析了来自多个DLBCL数据集（GSE83632、TCGA-GTEX、GSE181063、GSE4475）的转录组数据。使用临床样本、DLBCL细胞系和体内异种移植小鼠模型，验证了所确定的关键因子线粒体丙酮酸载体2（MPC2）的表达和功能。综合生物信息学分析确定MPC2是DLBCL中显著上调的基因，与氧化磷酸化（OXPHOS）和细胞周期相关基因的富集有关。在临床DLBCL样本和细胞系中，均在mRNA和蛋白质水平证实了MPC2的过表达。在DLBCL细胞中敲低MPC2会损害线粒体OXPHOS，增加糖酵解，并抑制细胞增殖、侵袭和三维球体形成。在体内，MPC2沉默显著降低了异种移植小鼠模型中的肿瘤生长。我们的研究结果揭示了MPC2是DLBCL中线粒体功能的关键调节因子，通过增强OXPHOS促进肿瘤进展。本研究为DLBCL的代谢重编程提供了新见解，并表明MPC2是这种侵袭性淋巴瘤的潜在治疗靶点。
