代谢相关脂肪性肝病（MAFLD）通过增强KIF20A表达促进肝细胞癌进展。

Metabolic-associated fatty liver disease (MAFLD) promotes the progression of hepatocellular carcinoma by enhancing KIF20A expression.

作者信息

Hu Xinsong, Chen Yifei, Ying Hao, He Cong, Ren Yangyang, Tian Yiqing, Tan Youwen

机构信息

School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China.

School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China; Department of Laboratory Medicine, Wujin Hospital Affiliated With Jiangsu University (The Wujin Clinical College of Xuzhou Medical University), Changzhou, Jiangsu, China.

出版信息

Int Immunopharmacol. 2025 May 8;154:114589. doi: 10.1016/j.intimp.2025.114589. Epub 2025 Mar 31.

DOI:10.1016/j.intimp.2025.114589

PMID:40168801

Abstract

BACKGROUND

Compared to other HCC, those related to MAFLD exhibit distinct prognostic differences. This article aims to elucidate the impact of MAFLD on HCC prognosis through the lens of KIF20A, thereby providing a theoretical foundation for targeted therapies in MAFLD-related HCC.

METHODS

We employed the Weighted gene co-expression network analysis (WGCNA) method alongside the Mime package to identify key genes associated with MAFLD-related HCC. Subsequently, we utilized OCLR and CytoTRACE algorithms to evaluate the relationship between these genes and HCC stemness. The R package was employed to conduct immunological analyses on both mRNA sequencing and single-cell data. We validated the effects of core genes on HCC through experimental approaches, including cell culture, Transwell assays, Western Blot, and proliferation assays. Finally, we predicted potential therapeutic drugs using the OncoPredict software package.

RESULTS

WGCNA identified the cyan module associated with MAFLD in GSE135251 and the blue module linked to HCC in TCGA. Further analysis identified KIF20A as the core gene in MAFLD-related HCC. Utilizing the OCLR and CytoTRACE algorithms, KIF20A was found to correlate with mRNA stemness index (mRNAsi). Analysis of public databases revealed that KIF20A promotes immune tolerance through the SPP1-CD44 pathway and drives HCC progression via the G2M checkpoint. Experimental results demonstrated that lipotoxic damage in HCC cells and small extracellular vesicles (sEVs) derived from these cells upregulate KIF20A, thereby accelerating HCC progression. Finally, OncoPredict and AutoDock were employed to predict drugs targeting KIF20A.

CONCLUSION

MAFLD-related HCC can elevate KIF20A levels and promote tumor proliferation and migration.

摘要

背景

与其他肝细胞癌（HCC）相比，与代谢相关脂肪性肝病（MAFLD）相关的HCC表现出明显的预后差异。本文旨在通过KIF20A这一视角阐明MAFLD对HCC预后的影响，从而为MAFLD相关HCC的靶向治疗提供理论基础。

方法

我们采用加权基因共表达网络分析（WGCNA）方法并结合Mime软件包来识别与MAFLD相关HCC相关的关键基因。随后，我们利用OCLR和CytoTRACE算法评估这些基因与HCC干性之间的关系。使用R软件包对mRNA测序和单细胞数据进行免疫分析。我们通过细胞培养、Transwell实验、蛋白质免疫印迹和增殖实验等实验方法验证核心基因对HCC的影响。最后，我们使用OncoPredict软件包预测潜在的治疗药物。

结果

WGCNA在GSE135251中识别出与MAFLD相关的青色模块，在TCGA中识别出与HCC相关的蓝色模块。进一步分析确定KIF20A为MAFLD相关HCC的核心基因。利用OCLR和CytoTRACE算法，发现KIF20A与mRNA干性指数（mRNAsi）相关。对公共数据库的分析表明，KIF20A通过SPP1-CD44途径促进免疫耐受，并通过G2M检查点驱动HCC进展。实验结果表明，HCC细胞中的脂毒性损伤以及源自这些细胞的小细胞外囊泡（sEVs）上调KIF20A，从而加速HCC进展。最后，使用OncoPredict和AutoDock预测靶向KIF20A的药物。