Qian Liqiang, Wang Gang, Li Bin, Su Haoyuan, Qin Lei
Department of General Surgery, Suzhou Ninth Hospital Affiliated to Soochow University, Suzhou, Jiangsu, China.
Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
PeerJ. 2024 Jan 22;12:e16740. doi: 10.7717/peerj.16740. eCollection 2024.
Intrahepatic cholangiocarcinoma (ICC) is a malignancy with a dismal prognosis, thus the discovery of promising diagnostic markers and treatment targets is still required. In this study, 1,852 differentially expressed genes (DEGs) were identified in the GSE45001 dataset for weighted gene co-expression network analysis (WGCNA), and the turquoise module was confirmed as the key module. Next, the subnetworks of the 1,009 genes in the turquoise module analyzed by MCODE, MCC, and BottleNeck algorithms identified nine overlapping genes (CAT, APOA1, APOC2, HSD17B4, EHHADH, APOA2, APOE4, ACOX1, AGXT), significantly associated with lipid metabolism pathways, such as peroxisome and cholesterol metabolism. Among them, APOE4 exhibited a potential tumor-suppressive role in ICC and high diagnostic value for ICC in both GSE45001 and GSE32879 datasets. experiments demonstrated Apolipoprotein E4 (APOE4) overexpression suppressed ICC cell proliferation, migration, and invasion, knockdown was the opposite trend. And in ICC modulated lipid metabolism, notably decreasing levels of TG, LDL-C, and HDL-C, while concurrently increasing the expressions of TC. Further, APOE4 also downregulated lipid metabolism-related genes, suggesting a key regulatory role in maintaining cellular homeostasis, and regulating the expression of the membrane protein ATP-binding cassette transporter A1 (ABCA1). These findings highlighted the coordinated regulation of lipid metabolism by APOE4 and ABCA1 in ICC progression, providing new insights into ICC mechanisms and potential therapeutic strategies.
肝内胆管癌（ICC）是一种预后不佳的恶性肿瘤，因此仍需要发现有前景的诊断标志物和治疗靶点。在本研究中，在GSE45001数据集中鉴定出1852个差异表达基因（DEG）用于加权基因共表达网络分析（WGCNA），并确认绿松石模块为关键模块。接下来，通过MCODE、MCC和瓶颈算法分析绿松石模块中1009个基因的子网络，鉴定出9个重叠基因（CAT、APOA1、APOC2、HSD17B4、EHHADH、APOA2、APOE4、ACOX1、AGXT），它们与脂质代谢途径如过氧化物酶体和胆固醇代谢显著相关。其中，APOE4在ICC中表现出潜在的肿瘤抑制作用，并且在GSE45001和GSE32879数据集中对ICC具有较高的诊断价值。实验表明，载脂蛋白E4（APOE4）过表达抑制ICC细胞增殖、迁移和侵袭，敲低则呈现相反趋势。并且在ICC中，APOE4调节脂质代谢，显著降低TG、LDL-C和HDL-C水平，同时增加TC的表达。此外，APOE4还下调脂质代谢相关基因，表明其在维持细胞内稳态以及调节膜蛋白ATP结合盒转运体A1（ABCA1）表达方面起关键调节作用。这些发现突出了APOE4和ABCA1在ICC进展过程中对脂质代谢的协同调节作用，为ICC的发病机制和潜在治疗策略提供了新的见解。
