Gao Ming, Ye Peng, Zhang Yutong, Guo Yarong, Xu Jun
Hepatobiliary and Pancreatic Surgery and Liver Transplantation Center, First Hospital of Shanxi Medical University, No. 85 Jiefang South Road, Taiyuan, Shanxi 030001, China.
Faculty of Graduate Studies, Shanxi Medical University, No. 56 Xinjian South Road, Taiyuan, Shanxi 030001, China.
Carcinogenesis. 2025 Apr 3;46(2). doi: 10.1093/carcin/bgaf019.
Gallbladder cancer (GBC) ranks as the most common malignant tumor of the biliary tract, which has been characterized by late diagnosis, low excisional rate, and poor prognosis. Recent studies exploring the roles of malignant progression-associated genes in GBC remain limited. Our study aims to identify significant hub genes involved in its pathogenesis, which may serve as novel potential therapeutic targets for GBC. Here, we employed RNA-seq analysis to identify differentially expressed genes (DEGs) of seven GBC samples and five matched adjacent samples. After screening the DEGs in clinical sequencing data and GSE139682, we further obtained 549 genes with consistent expression trends in two datasets, including 155 upregulated and 394 downregulated genes. Gene Ontology (GO) enrichment analysis revealed that these genes were significantly enriched in extracellular matrix (ECM)-related processes, such as organization, structure, and composition, which hint to us that remodeling of ECM may be the main driving factor for the malignant progression of GBC. In addition, we screened 17 candidate hub genes through protein-protein interaction (PPI) network analysis and Cytoscape, subsequent GO and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that the remodeled ECM mainly functions by affecting cell division. Moreover, we found that NEK2 and NUF2 were overexpressed in GBC tumor tissues and validated their function in the pro-proliferation of GBC cells. Our results highlight that NEK2 and NUF2 may be hub genes promoting the malignant progression of GBC and are expected to be reliable new therapeutic targets for GBC.
胆囊癌（GBC）是最常见的胆道恶性肿瘤，其特点是诊断晚、切除率低且预后差。目前关于恶性进展相关基因在胆囊癌中作用的研究仍然有限。我们的研究旨在确定参与其发病机制的重要枢纽基因，这些基因可能成为胆囊癌新的潜在治疗靶点。在此，我们采用RNA测序分析来鉴定7例胆囊癌样本和5例匹配的相邻样本中的差异表达基因（DEG）。在临床测序数据和GSE139682中筛选出DEG后，我们在两个数据集中进一步获得了549个表达趋势一致的基因，其中包括155个上调基因和394个下调基因。基因本体（GO）富集分析表明，这些基因在细胞外基质（ECM）相关过程中显著富集，如组织、结构和组成，这提示我们ECM重塑可能是胆囊癌恶性进展的主要驱动因素。此外，我们通过蛋白质-蛋白质相互作用（PPI）网络分析和Cytoscape筛选出17个候选枢纽基因，随后的GO和京都基因与基因组百科全书（KEGG）富集分析表明，重塑的ECM主要通过影响细胞分裂发挥作用。此外，我们发现NEK2和NUF2在胆囊癌肿瘤组织中过表达，并验证了它们在胆囊癌细胞增殖中的作用。我们的结果表明，NEK2和NUF2可能是促进胆囊癌恶性进展的枢纽基因，有望成为胆囊癌可靠的新治疗靶点。
