肝细胞癌中HIF-1α依赖性的ATP2C1过表达指示不良预后  

HIF-1α-dependent ATP2C1 Overexpression in Hepatocellular Carcinoma Predicting a Poor Prognosis

作　　者：任德续 马少杰 丁圆圆 王雅嵩 钱其兰 邱腾 陈泽锋 施雯 王伟玲 马金鸣 王秀军 吉敬 REN Dexu;MA Shaojie;DING Yuanyuan;WANG Yasong;QIAN Qilan;QIU Teng;CHEN Zefeng;SHI Wen;WANG Weiling;MA Jinming;WANG Xiujun;JI Jing(School of Pharmacy,Jiangsu Ocean University,Lianyungang 222005,China;Jiangsu Key Laboratory of Marine Drug Active Molecular Screening,Jiangsu Ocean University,Lianyungang 222005,China)

机构地区：[1]江苏海洋大学药学院,江苏连云港222005 [2]江苏海洋大学江苏省海洋药物活性分子筛选重点实验室,江苏连云港222005

出　　处：《江苏海洋大学学报（自然科学版）》2024年第1期44-57,共14页Journal of Jiangsu Ocean University:Natural Science Edition

摘　　要：缺氧诱导因子(hypoxia-inducible factor, HIF)与肝细胞癌的发生发展相关。HIF-1α在包括肝细胞癌在内的多种癌症类型的发生发展中发挥着重要作用,但其在肝细胞癌中的靶基因尚未完全确定。为找到HIF-1α在肝癌中新的致癌靶点,通过整合HIF-1α敲除的RNA-seq数据,HIF-1α的ChIP-Seq数据,HIF-1α在肝癌中的共表达基因,以及肝癌相关的GEO(Gene Expression Omnibus)数据集,寻找HIF-1α的潜在靶基因。通过分析TCGA(The Cancer Genome Atlas)肝癌数据库、GEO和HPA(Human Protein Atlas)数据集,研究HIF-1α与ATP2C1的相关性,ATP2C1在肝癌中的表达及预后。通过建立物理和化学(氯化钴)缺氧模型验证ATP2C1与低氧及HIF-1α的关系。通过GO(Gene Ontology),KEGG(Kyoto Encyclopedia of Genes and Genomes)和GSEA(Gene Set Enrichment Analysis)分析探索ATP2C1的生物学功能。通过设计体外实验证实ATP2C1对HCC的作用。利用STRING和BioGRID两个蛋白互作在线数据库获得ATP2C1的互作蛋白,并研究其在肝癌中的表达及相关性。通过整合及筛选数据,ATP2C1被鉴定为一个HIF-1α的潜在靶基因。ATP2C1与HIF-1α高度相关,在肝细胞癌中高表达,且伴随有不良预后。富集分析与体外实验的结果表明ATP2C1参与调控HCC细胞的增殖迁移。蛋白互作数据表明ATP2C1与TMEM165存在互作关系,生存分析表明TMEM1651高表达的肝癌患者预后较差。相关性分析的结果显示ATP2C1与肝癌中TMEM165和MMP2的表达高度相关,表明ATP2C1可能与TMEM165和MMP2存在互作关系,并参与了肝癌的进展过程。结果表明,ATP2C1是HIF-1α的靶基因和肝细胞癌的生物标志物,其敲低抑制了HCC的增殖和迁移。Hypoxia-inducible factors(HIF)are associated with the onset and progression of hepatocellular cancer.As an important member of the hypoxia-inducing factors,HIF-1αplays an important role in the occurrence and development of various cancer types,especially hepatocellular carcinoma.However,its target genes in hepatocellular carcinoma have not been fully determined.Therefore,this study aims to identify a new oncogenic target of HIF-1αin liver cancer.The publicly available RNA-Seq and ChIP-Seq data of HIF-1αwild-type(WT)and Knockout(KO)cells,co-expression genes of HIF-1αin HCC,and hepatocellular carcinoma-related Gene Expression Omnibus(GEO)data sets were integrated to search for potential target genes of HIF-1α.The correlation between HIF-1αand ATP2C1,and the expression and prognosis of ATP2C1 in liver cancer were investigated by analyzing The Cancer Genome Atlas(TCGA)database,GEO,and HPA(Human Protein Atlas)dataset.Physical and chemical(CoCl 2)hypoxia models were established to verify the relationship between ATP2C1 and hypoxia and HIF-1α.The biological function of ATP2C1was explored with Gene Ontology(GO),Kyoto Encyclopedia of Genes and Genomes(KEGG)and Gene Set Enrichment Analysis(GSEA).In vitro experiments were designed to confirm the role of ATP2C1 in HCC.The interaction proteins of ATP2C1 were obtained by using two online protein interaction databases,STRING and BioGRID,and their expression and correlation in HCC were studied.By integrating and screening the public data,ATP2C1 was identified as a potential target gene for HIF-1α,which was highly expressed in HCC and associated with poor prognosis.The results of enrichment analysis and in vitro experiments indicated that ATP2C1 was involved in the regulation of HCC cell proliferation and migration.Protein interaction data showed that ATP2C1 interacted with TMEM165.Survival analysis showed that HCC patients with high expression of TMEM1651 had a poor prognosis.The results of correlation analysis showed that ATP2C1 was highly correlated with TMEM165 and MM

关 键 词：缺氧 HIF-1Α ATP2C1 肝细胞癌 预后 

分 类 号：R965.1[医药卫生—药理学]