胃癌中FKBP1A高表达的预后价值及其靶向PI3K/AKT对糖代谢的调控作用

The prognostic value of high expression of FKBP1A in gastric cancer and the regulatory effect of targeted PI3K/AKT on glucose metabolism

背景与目的:胃癌是常见的消化道恶性肿瘤之一,FKBP脯氨酸异构酶1A(FKBP prolyl isomerase 1A,FKBP1A)参与多种肿瘤的发生、发展,但在胃癌中的生物学作用及机制尚未明确。本研究旨在探讨FKBP1A在胃癌组织中的表达水平及预后价值,分析其调控胃癌进展的可能途径和机制。方法:免疫组织化学观察FKBP1A在胃癌中的表达情况并结合生物信息学与临床病理学参数分析其与预后不良的相关性;采用Kaplan-Meier生存曲线描述FKBP1A对胃癌患者术后5年生存率的影响,采用COX多因素回归分析探讨影响胃癌患者术后生存率的独立预后因素;通过受试者工作特征(receiver operating characteristic,ROC)曲线分析FKBP1A表达在胃癌患者中的诊断价值;基因本体(Gene Ontology,GO)和京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)富集分析FKBP1A的生物学功能及可能参与的信号转导通路,体外构建慢病毒转染的MGC803细胞模型,探究FKBP1A对MGC803细胞糖代谢和恶性生物学行为的影响以及可能的分子机制,并构建裸鼠移植瘤模型加以验证。结果:免疫组织化学检测结果显示,FKBP1A在胃癌中呈高表达(P<0.01),生物信息学与临床参数分析结果显示,其与患者预后不良相关;Kaplan-Meier生存分析和COX回归分析显示,FKBP1A表达量与患者5年生存率呈负相关,且其与外周血癌胚抗原(carcinoembryonic antigen,CEA)≥5μg/L、糖类抗原19-9(carbohydrate antigen 19-9,CA19-9)≥37 kU/L、T分期(T3~T4期)和N分期(N2~N3期)是影响胃癌患者术后5年生存率的独立预后因素(P<0.05);ROC曲线分析表明,FKBP1A高表达具有较好的预后诊断价值(P<0.01);GO和KEGG富集分析推测FKBP1A可能参与调节胃癌细胞糖代谢。体外实验显示,过表达FKBP1A促进MGC803细胞糖代谢、增殖、侵袭和迁移,沉默FKBP1A则相反(P<0.05)。在体实验显示,胃癌细胞过表达FKBP1A促进裸鼠移植瘤的生长,而沉默则抑制之(P<0.05)。机制分析表明,过表达FKBP1A上调胃癌细胞中磷酸化的磷脂酰肌醇3激酶(phosphatidylinositol 3-kinase,PI3K)和磷酸化的蛋白激酶B(protein kinase B,AKT)的表达,而沉默则下调之(P<0.05)。结论:FKBP1A在胃癌组织中高表达且与患者预后不良相关,可能是通过激活PI3K/AKT促进胃癌细胞的糖代谢和恶性生物学行为。

Background and purpose:Gastric cancer is one of the common gastrointestinal malignancies.FKBP1A has been reported to be involved in the occurrence and development of various tumors,but the biological role and mechanism of it in gastric cancer remain unclear.This study aimed to investigate the expression level and prognostic value of FKBP1A in gastric cancer tissues,and to analyze the possible pathways and mechanisms of its regulation of gastric cancer progression.Methods:The expression of FKBP1A in gastric cancer was observed by immunohistochemistry,and its correlation with poor prognosis was analyzed by combining bioinformatics and clinicopathological parameters.Kaplan-Meier survival curve was used to analyze the effect of FKBP1A on the 5-year survival rate of patients with gastric cancer after surgery,and COX multivariate regression analysis was used to explore the independent prognostic factors affecting the 5-year survival rate of patients with gastric cancer after surgery.The diagnostic value of FKBP1A expression in patients with gastric cancer was analyzed using receiver operating characteristic(ROC)curve.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)were used to enrich and analyze the biological function of FKBP1A and the possible signal pathways involved.We constructed the MGC803 cell model transfected with lentivirus in vitro,explored the influence of FKBP1A on the glucose metabolism and malignant biological behavior of MGC803 cells,and the possible molecular mechanism involved,and established a nude mouse transplantation tumor model in vitro to verify it.Results:Immunohistochemical results showed that FKBP1A was highly expressed in gastric cancer(P<0.01),and bioinformatics and clinical parameter analysis showed that FKBP1A was associated with poor prognosis.Kaplan-Meier survival analysis and COX regression analysis showed that the expression level of FKBP1A was negatively correlated with 5-year survival.And carcinoembryonic antigen(CEA)≥5μg/L,carbohydrate antigen(CA)19-9≥37 kU/L,T stage(T3-T4)and N stage(N2-N3)were independent prognostic factors affecting the 5-year survival rate of gastric cancer patients after surgery(P<0.05).ROC analysis showed that high expression of FKBP1A had good prognostic value(P<0.01).Enrichment of GO and KEGG suggested that FKBP1A was involved in regulating glucose metabolism in gastric cancer cells.In vitro experiments showed that overexpression of FKBP1A promoted glucose metabolism and proliferation,invasion and migration of MGC803 cells,while silencing of FKBP1A did the opposite(P<0.05).In vivo experiments showed that overexpression of FKBP1A in gastric cancer cells promoted the growth of transplanted tumor in nude mice,while silencing FKBP1A inhibited it(P<0.05).Mechanism analysis showed that overexpression of FKBP1A upregulated the expressions of phosphatidylinositol 3-kinase(PI3K)and protein kinase B(AKT)in gastric cancer cells,while silencing FKBP1A downregulated the expressions(P<0.05).Conclusion:FKBP1A is highly expressed in gastric cancer tissues,and is associated with poor prognosis,which may be due to the promotion of glucose metabolism and malignant biological behavior of gastric cancer cells by activating PI3K/AKT.