Yang Mengting, Han Xiu, Li Hongxu, Du Fengyi, Feng Chunlai, Gong Aihua
Hematological Disease Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, China, 212001.
Center of Clinical Laboratory, Dushu Lake Hospital Affiliated to Soochow University, Medical Center of Soochow University, Suzhou Dushu Lake Hospital, Suzhou, Jiangsu, China, 215213.
J Cancer. 2025 Jan 6;16(4):1101-1117. doi: 10.7150/jca.98452. eCollection 2025.
Glioblastoma multiforme (GBM), whose pathogenesis involves proneural-to-mesenchymal transition (PMT), is the most malignant type of glioma and is associated with a bleak prognosis. Lactate dehydrogenase (LDH) comprises two major subunits, LDHA and LDHB, which can assemble into five different isoenzymes (LDH1-5). However, the role of LDH isoenzyme and its subunits in different GBM subtypes is largely unknown. Our findings reveal that LDHA and LDHB subunits correlated with mesenchymal and proneural subtype classification, and have prognostic and clinical significance in GBM patients. Moreover, it is demonstrated that LDH5, characterized by high LDHA and low LDHB levels, is highly expressed in mesenchymal subtype GBM cells and promotes proliferation, migration, and PMT. Conversely, proneural subtype GBM cells exhibited LDH1 dominance, and low LDHA and high LDHB levels. Notably, LDH1 played a pivotal role in the proliferation, migration, and PMT of proneural glioma cells. For treatment of proneural subtype GBM, gossypol-acetic acid (GAA)-bovine serum albumin (BSA) nanoparticles (GAA-BSA NPs) were developed to ameliorate PMT by targeting LDH1. These nanoparticles effectively suppress proneural subtype tumor growth both and , surpassing their efficacy against the mesenchymal subtype. The results offer several novel insights into the role of LDH isoenzyme in subtype classification between mesenchymal and proneural GBM and provide a promising therapeutic approach for proneural subtype GBM.
多形性胶质母细胞瘤（GBM）是最恶性的胶质瘤类型，其发病机制涉及神经前体细胞向间充质细胞的转变（PMT），预后较差。乳酸脱氢酶（LDH）由两个主要亚基LDHA和LDHB组成，它们可组装成五种不同的同工酶（LDH1 - 5）。然而，LDH同工酶及其亚基在不同GBM亚型中的作用尚不清楚。我们的研究结果表明，LDHA和LDHB亚基与间充质和神经前体亚型分类相关，对GBM患者具有预后和临床意义。此外，以高LDHA和低LDHB水平为特征的LDH5在间充质亚型GBM细胞中高表达，促进细胞增殖、迁移和PMT。相反，神经前体亚型GBM细胞表现为LDH1占主导，LDHA水平低，LDHB水平高。值得注意的是，LDH1在神经前体胶质瘤细胞的增殖、迁移和PMT中起关键作用。为了治疗神经前体亚型GBM，开发了棉酚乙酸（GAA）-牛血清白蛋白（BSA）纳米颗粒（GAA - BSA NPs），通过靶向LDH1来改善PMT。这些纳米颗粒在体内和体外均能有效抑制神经前体亚型肿瘤的生长，其疗效超过了对间充质亚型的效果。这些结果为LDH同工酶在间充质和神经前体GBM亚型分类中的作用提供了新的见解，并为神经前体亚型GBM提供了一种有前景的治疗方法。
