伏马菌素B2毒素与Akt1在大骨节病发病机制中对基因表达调控的相互作用

The interaction of HT-2 toxin and Akt1 on gene expression regulation in Kashin-Beck disease pathogenesis.

作者信息

Liao Xinhua, Yang Xiaodong, Jia Xiaoqian, Zhang Qian, Naren Gaowa, Zhang Jiaojiao, Niu Hui, Wei Haiyan, Wu Cuiyan

机构信息

General Surgery Department, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, PR China.

Shaanxi Provincial Center for Disease Prevention and Control, Xi'an, 710054, Shaanxi, PR China.

出版信息

Toxicon. 2025 Sep;264:108432. doi: 10.1016/j.toxicon.2025.108432. Epub 2025 May 29.

DOI:10.1016/j.toxicon.2025.108432

PMID:40449756

Abstract

BACKGROUND

This study investigates the effects of T-2 toxin metabolite HT-2 alone or combined with Akt1 on chondrocyte gene expression to elucidate their roles in Kashin-Beck disease (KBD) pathogenesis.

METHODS

Lentiviral transfection was employed to silence Akt1 in C28/I2 human chondrocytes. High-throughput RNA sequencing and bioinformatics analysis methods were used to identify and compare differentially expressed genes (DEGs) and pathways in HT-2, siAkt1, HT-2-siAkt1 and Control (non-treatment) group. Co-expressed genes and co-expressed modules were investigated using WGCNA. Protein-protein interaction (PPI) networks were constructed using the STRING database, and hub genes were identified by the MCC algorithm.

RESULTS

A total of 2086 DEGs were identified in the HT-2 vs Control comparison, with significant upregulation observed for CCND2, MMP9 and TIMP4. The adhesion and PI3K-Akt signaling pathways were upregulated, while ECM-receptor interactions was downregulated. In the siAkt1 vs Control comparison, 695 DEGs were detected. VAMP7 and CXCR4 were significantly upregulated, while PFKL and ALDOA were significantly downregulated. Fructose and mannose metabolism, amino acid biosynthesis, and glucose/energy metabolic pathways were significantly downregulated. There were 411 DEGs when HT-2-siAkt1 vs HT-2, and CCND2, MMP9, WTAPP1 and TIMP4 were significantly downregulated. Adhesion, NF-κB signaling pathway and PI3K-Akt signaling pathway were significantly downregulated. Under, WGCNA, in the module most associated with HT-2, FRMD3B, ALDH1A3, ANTXR2, SERINC2 and SRGN were identified as hub genes; in the module most associated with siAkt1, TNFRSF11B, CECR2, TMOD1, ZNF704 and RHOBTB1 were identified as hub genes; in the module most associated with HT-2-siAkt1, the hub genes were GNAL, SLC25A32, ACADSB, CABLES1 and GINS4.

CONCLUSION

Akt1 primarily affects the expression of genes in chondrocytes under HT-2 exposure that involved in autophagy, cell proliferation and glycolysis and other cell functions, potentially contributing to the pathogenesis of KBD.

摘要

背景

本研究调查T-2毒素代谢物HT-2单独作用或与Akt1联合作用对软骨细胞基因表达的影响，以阐明它们在大骨节病（KBD）发病机制中的作用。

方法

采用慢病毒转染法沉默C28/I2人软骨细胞中的Akt1。运用高通量RNA测序和生物信息学分析方法，鉴定并比较HT-2、siAkt1、HT-2-siAkt1组和对照组（未处理）中差异表达基因（DEG）和信号通路。使用WGCNA研究共表达基因和共表达模块。利用STRING数据库构建蛋白质-蛋白质相互作用（PPI）网络，并通过MCC算法鉴定枢纽基因。

结果

在HT-2与对照组的比较中，共鉴定出2086个DEG，其中CCND2、MMP9和TIMP4显著上调。黏附及PI3K-Akt信号通路上调，而ECM-受体相互作用下调。在siAkt1与对照组的比较中，检测到695个DEG。VAMP7和CXCR4显著上调，而PFKL和ALDOA显著下调。果糖和甘露糖代谢、氨基酸生物合成及葡萄糖/能量代谢通路显著下调。HT-2-siAkt1与HT-2比较时有411个DEG，CCND2、MMP9、WTAPP1和TIMP4显著下调。黏附、NF-κB信号通路和PI3K-Akt信号通路显著下调。在WGCNA分析中，在与HT-2最相关的模块中，FRMD3B、ALDH1A3、ANTXR2、SERINC2和SRGN被鉴定为枢纽基因；在与siAkt1最相关的模块中，TNFRSF11B、CECR2、TMOD1、ZNF704和RHOBTB1被鉴定为枢纽基因；在与HT-2-siAkt1最相关的模块中，枢纽基因是GNAL、SLC25A32、ACADSB、CABLES1和GINS4。