Zhang Weiming, Yu Nasha, Song Xiangxiang, Zhong Xing
Departments of Lymphatic and Hematological Oncology, Jiangxi Cancer Hospital (The Second Affiliated Hospital of Nanchang Medical College), No. 519, Beijing East Road, Nanchang, 330029, Jiangxi, China.
JXHC Key Laboratory of Tumor Microenvironment and Immunoregulation (Jiangxi Cancer Hospital), Nanchang, 330029, Jiangxi, China.
Hum Cell. 2025 Aug 7;38(5):139. doi: 10.1007/s13577-025-01267-y.
Diffuse large B-cell lymphoma (DLBCL) is a malignant tumor and research on its therapeutic targets has received increasing attention. It has been reported that Leucyl-tRNA synthetase (LARS) contributes to the growth and migration of non-Hodgkin lymphoma (NHL), yet its effect on DLBCL progression remains to be elucidated. MTT and flow cytometry were carried out to determine the cellular phenotypes of DLBCL cells under LARS overexpression. The differentially expressed proteins (DEPs) were screened by mass spectrometry. ELISA, western blot, and xenograft tumor experiments were implemented to confirm the impact of LARS and the LRPPRC/HIF-1α axis on malignant progression and glycolysis. Dual-luciferase reporter assay and chromatin immunoprecipitation (ChIP) were applied for exploring the underlying mechanism by which LARS was regulated. LARS promoted the malignant phenotypes, such as increasing cell proliferation and inhibiting apoptosis, and enhanced abnormal glycolysis both in vitro and in vivo. Based on mass spectrometry and functional recovery experiments, we found that LARS upregulated LRPPRC expression. More importantly, overexpressing LRPPRC facilitated malignant phenotypes and glycolysis through the elevation of HIF-1α expression, which could be reversed by silenced HIF-1α. Mechanistically, LARS promoted the expression of HIF-1α by activating LRPPRC, which in turn enhanced the transcription of HK2, thereby facilitating malignant progression and abnormal glycolysis. LARS facilitated abnormal glycolysis via the LRPPRC/HIF-1α/HK2 axis, thereby promoting the malignant progression of DLBCL.
弥漫性大B细胞淋巴瘤（DLBCL）是一种恶性肿瘤，对其治疗靶点的研究受到越来越多的关注。据报道，亮氨酰-tRNA合成酶（LARS）有助于非霍奇金淋巴瘤（NHL）的生长和迁移，但其对DLBCL进展的影响仍有待阐明。进行MTT和流式细胞术以确定LARS过表达下DLBCL细胞的细胞表型。通过质谱筛选差异表达蛋白（DEP）。实施ELISA、蛋白质印迹和异种移植肿瘤实验以证实LARS和LRPPRC/HIF-1α轴对恶性进展和糖酵解的影响。应用双荧光素酶报告基因检测和染色质免疫沉淀（ChIP）来探索LARS被调控的潜在机制。LARS促进恶性表型，如增加细胞增殖和抑制细胞凋亡，并在体外和体内增强异常糖酵解。基于质谱和功能恢复实验，我们发现LARS上调LRPPRC表达。更重要的是，过表达LRPPRC通过提高HIF-1α表达促进恶性表型和糖酵解，而沉默HIF-1α可逆转这种情况。机制上，LARS通过激活LRPPRC促进HIF-1α的表达，进而增强HK2的转录，从而促进恶性进展和异常糖酵解。LARS通过LRPPRC/HIF-1α/HK2轴促进异常糖酵解，从而促进DLBCL的恶性进展。
