Li Fengwei, Chen Qinjunjie, Yang Yang, Li Meihui, Zhang Lei, Yan Zhenlin, Zhang Junjie, Wang Kui
Department of Hepatic Surgery (II) of the Eastern Hepatobiliary Surgery Hospital, Navy Medical University, (Second Military Medical University), #225 Changhai Road, Shanghai, 200438, China.
Department of Hepatic Surgery (IV) of the Eastern Hepatobiliary Surgery Hospital, Navy Medical University, Shanghai, China.
Cancer Cell Int. 2021 Apr 17;21(1):225. doi: 10.1186/s12935-021-01929-5.
Intrahepatic cholangiocarcinoma (iCCA) is the second most common malignant hepatic tumor and has a high postoperative recurrence rate and a poor prognosis. The key roles of most tumor recurrence-associated molecules in iCCA remain unclear. This study aimed to explore hub genes related to the postsurgical recurrence of iCCA.
Differentially expressed genes (DEGs) between iCCA samples and normal liver samples were screened from The Cancer Genome Atlas (TCGA) database and used to construct a weighted gene coexpression network. Module-trait correlations were calculated to identify the key module related to recurrence in iCCA patients. Genes in the key module were subjected to functional enrichment analysis, and candidate hub genes were filtered through coexpression and protein-protein interaction (PPI) network analysis. Validation studies were conducted to detect the "real" hub gene. Furthermore, the biological functions and the underlying mechanism of the real hub gene in iCCA tumorigenesis and progression were determined via in vitro experiments.
A total of 1019 DEGs were filtered and used to construct four coexpression modules. The red module, which showed the highest correlations with the recurrence status, family history, and day to death of patients, was identified as the key module. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses demonstrated that genes in the red module were enriched in genes and pathways related to tumorigenesis and tumor progression. We performed validation studies and identified estrogen receptor 1 (ESR1), which significantly impacted the prognosis of iCCA patients, as the real hub gene related to the recurrence of iCCA. The in vitro experiments demonstrated that ESR1 overexpression significantly suppressed cell proliferation, migration, and invasion, whereas ESR1 knockdown elicited opposite effects. Further investigation into the mechanism demonstrated that ESR1 acts as a tumor suppressor by inhibiting the JAK/STAT3 signaling pathway.
ESR1 was identified as the real hub gene related to the recurrence of iCCA that plays a critical tumor suppressor role in iCCA progression. ESR1 significantly impacts the prognosis of iCCA patients and markedly suppresses cholangiocarcinoma cell proliferation, migration and invasion by inhibiting JAK/STAT3 signaling pathway.
肝内胆管癌（iCCA）是第二常见的肝脏恶性肿瘤，术后复发率高且预后较差。大多数与肿瘤复发相关的分子在iCCA中的关键作用仍不清楚。本研究旨在探索与iCCA术后复发相关的枢纽基因。
从癌症基因组图谱（TCGA）数据库中筛选iCCA样本与正常肝脏样本之间的差异表达基因（DEG），并用于构建加权基因共表达网络。计算模块-性状相关性以识别与iCCA患者复发相关的关键模块。对关键模块中的基因进行功能富集分析，并通过共表达和蛋白质-蛋白质相互作用（PPI）网络分析筛选候选枢纽基因。进行验证研究以检测“真正的”枢纽基因。此外，通过体外实验确定真正的枢纽基因在iCCA肿瘤发生和进展中的生物学功能及潜在机制。
共筛选出1019个DEG并用于构建四个共表达模块。红色模块与患者的复发状态、家族史和死亡天数显示出最高的相关性，被确定为关键模块。基因本体论（GO）富集分析和京都基因与基因组百科全书（KEGG）通路分析表明，红色模块中的基因在与肿瘤发生和肿瘤进展相关的基因和通路中富集。我们进行了验证研究，并确定雌激素受体1（ESR1）为与iCCA复发相关的真正枢纽基因，ESR1对iCCA患者的预后有显著影响。体外实验表明，ESR1过表达显著抑制细胞增殖、迁移和侵袭，而ESR1敲低则产生相反的效果。对机制的进一步研究表明，ESR1通过抑制JAK/STAT3信号通路发挥肿瘤抑制作用。
ESR1被确定为与iCCA复发相关的真正枢纽基因，在iCCA进展中起关键的肿瘤抑制作用。ESR1显著影响iCCA患者的预后，并通过抑制JAK/STAT3信号通路明显抑制胆管癌细胞的增殖、迁移和侵袭。
