胃癌组织中碳酸酐酶Ⅸ表达的临床意义及分子机制

Clinical significance of carbonic anhydraseⅨexpression in gastric cancer tissues and its molecular mechanisms

目的探讨胃癌(GC)组织中碳酸酐酶(CAⅨ)的临床意义及其分子机制。方法采用基因表达谱动态数据分析(GEPIA2)数据库预测GC组织中CAⅨ基因的差异性表达,利用癌症数据分析(UALCAN)数据库分析CAⅨ表达与GC患者临床病理特征的关系,采用Kaplan-Meier Plotter分析CAⅨ对GC的预后价值;收集10例GC患者的癌患组织(GC组)及其癌旁组织标本(对照组),采用免疫组织化学法检测CAⅨ表达;采用交互式基因检索工具(STRING)和可视代综合发现(DAVID)数据库进行基因本体论(GO)及京都基因与基因组百科全书(KEGG)通路分析预测CAⅨ的蛋白质互作关系及调控网络。结果GEPIA2数据库结果显示,与对照组比较,GC组CAⅨ的表达量降低(P<0.05);UALCAN数据库显示,CAⅨ的表达与种族、肿瘤分化等级、幽门螺杆菌感染有相关性(P<0.05);Kaplan-Meier Plotter数据库分析显示,低CAⅨ表达组与高CAⅨ表达组的5年无进展生存期(PFS)相比,差异有统计学意义(P<0.05);临床标本免疫组织化学结果显示,GC组标本中CAⅨ表达量较对照组降低(P<0.05),与数据库预测结果一致;STRING数据库分析显示,CAⅨ与缺氧诱导因子-1α(HIF1α)、溶质载体家族4成员4(SLC4A4)、芳烃受体核转位器(ARNT)等蛋白具有较强相互作用关系;GO分析显示,CAⅨ参与低氧反应下RNA聚合酶Ⅱ启动子的转录调节等过程;KEGG分析显示CAⅨ与癌症信号通路、缺氧诱导因子-1(HIF-1)信号通路的调节有关。结论CAⅨ在GC组织中呈低表达,其水平与GC患者肿瘤分化等级、PFS呈负相关,CAⅨ可能参与肿瘤代谢过程。

Objective To investigate clinical significance and molecular mechanism of carbonic anhydrase(CAⅨ)in gastric cancer(GC)tissues based on data mining analysis.Methods The GEPIA2 database was used to predict the differential expression of CAⅨgene in GC tissues,the UALCAN database was used to analyze the relationship between CAⅨexpression and the clinicopathological characteristics of GC patients,and the Kaplan-Meier Plotter was used to analyze the prognostic value of CAⅨon GC;cancerous tissues from 10 GC patients(GC group)and their paracancerous tissue specimens(the expression of CAⅨwas detected by immunohistochemistry in GC group and their paraneoplastic tissues(as the control group);the gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analyses were performed by STRING and DAVID databases to predict the protein interactions and regulatory networks of CAⅨ.Results GEPIA2 database showed that the expression of CAⅨwas reduced in GC group compared with the control group(P<0.05).The UALCAN database showed that the expression of CAⅨwas correlated with race,tumour differentiation grade and H.pylori infection(P<0.05);The Kaplan-Meier Plotter database analysis showed a statistically significant difference in 5-year progression-free survival(PFS)between the low CAⅨ-expressing group and the high CAⅨ-expressing group(P<0.05).The immunohistochemical results of clinical specimens showed that CAⅨexpression was significantly lower in the cancerous tissues of GC group compared with the paracancerous tissues of the control group(P<0.05),which was consistent with the predicted results of the database.The STRING database showed that CAⅨhad strong interactions with hypoxia-inducible factor-1a(HIF1A),solute carrier family 4 member 4(SLC4A4)and arylhydrocarbon receptor nuclear translocator(ARNT)proteins.The GO analysis of CAⅨand interacting proteins showed involvement in processes such as transcriptional regulation of RNA polymeraseⅡpromoter in response to hypoxia.KEGG analysis of CAⅨshowed it was associated with the cancer signalling pathway and the regulation of hypoxia-inducible factor-1(HIF-1)signalling pathway.Conclusion CAⅨis lowly expressed in GC tissues,and its level is negatively correlated with tumour differentiation grade and PFS in GC patients,and can be involved in tumour metabolic pathways.