肝内胆管癌(ICC)是一种预后不良的恶性肿瘤,因此,仍然需要发现有希望的诊断标志物和治疗靶标。在这项研究中,在GSE45001数据集中鉴定了1,852个差异表达基因(DEGs),用于加权基因共表达网络分析(WGCNA),绿松石模块被确认为关键模块。接下来,MCODE分析的绿松石模块中的1,009个基因的子网络,MCC,BottleNeck算法确定了9个重叠基因(CAT,APOA1,APOC2,HSD17B4,EHHADH,APOA2,APOE4,ACOX1,AGXT),与脂质代谢途径显着相关,如过氧化物酶体和胆固醇代谢。其中,在GSE45001和GSE32879数据集中,APOE4在ICC中表现出潜在的肿瘤抑制作用和对ICC的高诊断价值。体外实验证明载脂蛋白E4(APOE4)过表达抑制ICC细胞增殖,迁移,和入侵,击倒是相反的趋势。而在ICC调节脂质代谢中,显著降低TG水平,LDL-C,和HDL-C,同时增加TC的表达式。Further,APOE4也下调脂质代谢相关基因,表明在维持细胞稳态中的关键调节作用,并调节膜蛋白ATP结合盒转运蛋白A1(ABCA1)的表达。这些发现强调了在ICC进展中APOE4和ABCA1对脂质代谢的协调调节。提供对ICC机制和潜在治疗策略的新见解。
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. In vitro 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.