LDHB在肝细胞癌索拉非尼耐药中的作用及相关机制研究

Research of the Role of LDHB in Sorafenib Resistance in Hepatocellular Carcinoma and Its Related Mechanism

目的 通过生物信息学分析研究索拉非尼(sorafenib)耐药及敏感的肝癌细胞间基因表达的差异,找出关键的差异表达基因,从而预测在肝细胞癌对索拉非尼耐药发生发展中的关键基因。方法 从GEO数据库中下载GSE26391基因数据(包含4个对索拉非尼敏感的肝癌细胞样本,4个对索拉非尼耐药的肝癌细胞样本)。利用Morpheus在线软件分析,筛选出差异表达基因。运用Human Protein Atlas数据库分析差异表达基因乳酸脱氢酶B(LDHB)在肝癌与正常肝组织中的蛋白表达水平。并进一根据LDHB在肝癌患者中的表达高低进行分组后行生存分析。利用在线数据库LinkedOmics分析肝癌中与LDHB表达相关的靶基因。结果 基因芯片GSE26391数据分析显示,相比于对索拉非尼敏感肝癌细胞,在索拉非尼耐药肝癌细胞中LDHB表达上调。Human Protein Atlas数据库分析显示,与正常肝组织相比,LDHB在肝细胞癌组织中表达上调。生存分析显示,LDHB高表达的肝癌患者预后相对较差。LinkedOmics数据库分析显示Vimentin、ZEB1、ZEB2、Snial等EMT相关关键蛋白与LDHB表达正相关。结论 LDHB通过上调Vimentin、ZEB1、ZEB2、Snial蛋白,可能促进EMT的发生,从而介导肝癌中索拉非尼的耐药。

OBJECTIVE To investigate the differences in gene expression between sorafenib-resistant and sorafenib-sensitive hepatocellular carcinoma cells through bioinformatics analysis,and identify key differentially expressed genes.Finally,the key genes contribute to the development of sorafenib resistance in hepatocellular carcinoma are predicted.METHODS The gene data of GSE26391(including 4 sorafenib-sensitive and 4 sorafenib-resistant HCC cell samples)were downloaded from the GEO database.Differentially expressed genes were screened out by the analysis of online software Morpheus.The Human Protein Atlas database was used to analyze the protein expression level of LDHB in HCC tissues and normal liver tissues.Furthermore,survival analysis was performed after grouping according to the expression level of LDHB in liver cancer patients. Target genes associated with LDHB expression in HCC wereanalyzed using the online database LinkedOmics. RESULTS Analysis of gene chip GSE26391data showed that LDHB expression was up-regulated in sorafenib-resistant hepatoma cellscompared to sorafenib-sensitive hepatoma cells. Analysis of the Human Protein Atlas databaserevealed that LDHB was up-regulated in HCC tissues compared with normal liver tissues.Survival analysis showed that the prognosis of HCC patients with higher LDHB expression wasrelatively poorer. LinkedOmics database analysis showed that EMT-related key proteins such asVimentin, ZEB1, ZEB2, Snial were positively correlated with the expression of LDHB.CONCLUSION LDHB may promote the occurrence of EMT by up-regulating Vimentin, ZEB1,ZEB2 and Snial proteins, leading to sorafenib resistance in HCC.