Younis Osama M, Dhaydel Abdalrahman S, Alghwyeen Wasfi F, Abu Hantash Noor R, Allan Leen M, Qasem Issam M, Saeed Anwaar
Division of Hematology & Oncology, Department of Medicine, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, United States of America.
School of Medicine, The Hashemite University, Al Zarqaa, Jordan.
PLoS One. 2025 Apr 15;20(4):e0320343. doi: 10.1371/journal.pone.0320343. eCollection 2025.
Angiopoietin-like protein 4 (ANGPTL4) plays a crucial role in processes such as angiogenesis, inflammation, and metabolism. Despite numerous studies suggesting its involvement in cancer, a definitive role remains unclear. We introduce the first comprehensive meta-analysis and pan-cancer bioinformatics study on ANGPTL4, aiming to unravel its implications across various cancer types.
Moderate-to high-quality observational studies were retrieved from PubMed, Scopus, and Embase. A meta-analysis was conducted using the R package "meta." Survival analysis was performed using GEPIA2 and TIMER2.0. Immune infiltration, mutational burden, and drug resistance analyses was done via GSCAlite. Co-expression and gene set enrichment analyses (GSEA) were carried out using cBioportal and enrichr, respectively.
Increased ANGPTL4 expression was linked to worse tumor grade (OR = 1.51, P = 0.023), stage (OR = 2.42, P < 0.001), lymph node metastasis (OR = 1.76, P = 0.012), vascular invasion (OR = 2.16, P = 0.01), and lymphatic invasion (OR = 2.20, P < 0.001). Furthermore, ANGPTL4 expression was linked to worse OS (HR = 1.40, 95% CI: 1.29,1.50, P = 0.0001). Single gene level analysis revealed that ANGPTL4 upregulated epithelial-to-mesenchymal transition (EMT) in 23 different cancers. Immune infiltration varied between cancer types, but increased infiltration of cancer-associated fibroblasts was observed in most cancers. Mutation analysis revealed increased alterations in TP53 and CDKN2A in cohorts with ANGPTL4 alterations. GSEA of co-expressed genes revealed involvement in hypoxia, EMT, VEGF-A complex, TGF-B pathways, and extracellular matrix organization.
ANGPTL4 plays a significant role in tumor progression via its positive regulation of EMT and angiogenesis, while possibly harboring a TGF-B dependent role in systemic metastasis. Therefore, ANGPTL4 is a suitable target for future drug development.
血管生成素样蛋白4（ANGPTL4）在血管生成、炎症和代谢等过程中发挥着关键作用。尽管众多研究表明其与癌症有关，但其确切作用仍不明确。我们开展了第一项关于ANGPTL4的全面荟萃分析和泛癌生物信息学研究，旨在揭示其在各种癌症类型中的影响。
从PubMed、Scopus和Embase检索中到高质量的观察性研究。使用R包“meta”进行荟萃分析。使用GEPIA2和TIMER2.0进行生存分析。通过GSCAlite进行免疫浸润、突变负担和耐药性分析。分别使用cBioportal和enrichr进行共表达和基因集富集分析（GSEA）。
ANGPTL4表达增加与肿瘤分级较差（OR = 1.51，P = 0.023）、分期较差（OR = 2.42，P < 0.001）、淋巴结转移（OR = 1.76，P = 0.012）、血管侵犯（OR = 2.16，P = 0.01）和淋巴管侵犯（OR = 2.20，P < 0.001）相关。此外，ANGPTL4表达与较差的总生存期（HR = 1.40，95% CI：1.29，1.50，P = 0.0001）相关。单基因水平分析显示，ANGPTL4在23种不同癌症中上调上皮-间质转化（EMT）。免疫浸润在不同癌症类型之间有所不同，但在大多数癌症中观察到癌症相关成纤维细胞的浸润增加。突变分析显示，在有ANGPTL4改变的队列中，TP53和CDKN2A的改变增加。共表达基因的GSEA显示参与缺氧、EMT、VEGF-A复合物、TGF-B途径和细胞外基质组织。
ANGPTL4通过对EMT和血管生成的正向调节在肿瘤进展中发挥重要作用，同时可能在全身转移中具有依赖TGF-B的作用。因此，ANGPTL4是未来药物开发的合适靶点。
