碳水化合物磺基转移酶1的表达在胃癌中的预后价值及机制

Prognostic value of carbohydrate sulfotransferase 1 in stomach adenocarcinoma and underlying mechanism

目的探讨碳水化合物磺基转移酶1(CHST1)作为胃癌(STAD)分子标志物靶点的潜在临床价值。方法从癌症基因组图谱(TCGA)及基因表达储存(GEO)数据库获取胃癌患者CHST1 mRNA表达及临床资料数据。探索CHST1的表达水平,并体外组化实验验证其蛋白表达水平;随后探索CHST1的表达模式,利用Kaplan-Meier(KM)分析、受试者工作特征曲线(ROC)分析、Cox回归、诺模分析评估CHST1在胃癌中的预后价值;通过基因集富集分析(GSEA)及免疫浸润分析探索CHST1相关作用机制。结果TCGA数据显示,与正常组比较,CHST1在胃癌患者中明显高表达(P<0.05),免疫组织化学同样发现其在肿瘤中表达上调,且其表达水平与肿瘤分级有关(P<0.05);生存分析显示CHST1高表达明显缩短了患者总体生存时间[风险比(HR)=1.64,P<0.05],可独立预测患者生存(HR=1.632,P<0.05),且CHST1预测患者1、3、5年生存率的性能较好。此外,年龄与CHST1的预后价值有关,该基因主要影响年龄≤60岁患者的生存(HR=3.250,P<0.05)。CHST1的表达模式及预后价值均已在GEO数据集中得以验证(P<0.05)。GSEA分析发现CHST1高表达时,主要与ECM受体相互作用、黏着斑、细胞黏附分子(CAMs)等转移相关通路有关(P<0.05)。由于免疫微环境与肿瘤转移密切相关,本研究进一步研究了CHST1对胃癌免疫微环境的调控作用,发现CHST1与多数免疫细胞的浸润水平具有明显相关性;特别地,CHST1高表达抑制了激活型CD4_T细胞浸润、促进了M0巨噬细胞及肥大细胞浸润(P<0.05),且CHST1表达水平与此类细胞的相关免疫检查点基因间具有明显相关性(P<0.05)。结论CHST1在胃癌中高表达且不利于患者预后,且该基因可能通过调控免疫微环境参与胃癌的侵袭转移。

Objective To explore the potential of carbohydrate sulfotransferase 1(CHST1)as a novel biomarker in stomach adenocarcinoma(STAD).Methods We obtained the CHST1 expression value and clinical data of patients with STAD from the cancer genome atlas(TCGA)and Gene Expression Omnibus(GEO)databases.Then we explored the expression of CHST1,followed by the expression confirmation of CHST1 protein through immunohistochemistry(IHC).The prognostic value of CHST1 was assessed by Kaplan-Meier(KM),receiver operating characteristic(ROC)curve,Cox regression,and nomogram analyses.The gene set enrichment analysis(GSEA)and immune infiltration analysis were used to explore the CHST1-associated mechanism.Results From the TCGA data,CHST1 expression was higher in STAD group than that in normal group(P<0.05),and IHC further confirmed the upregulation of STAD.It was also found that CHST1 expression was related to the tumor grade(P<0.05).Survival analysis indicated that high expression of CHST1 significantly shortened the overall survival time of patients[hazard ration(HR)=1.64,P<0.001]and could independently predict the prognosis(HR=1.632,P<0.05).The CHST1 showed the favorable performance for predicting the 1-,3-,and 5-year survival.In addition,age was related to the prognostic value of CHST1 and it significantly affected the survival of patients with age≤60 years old(HR=3.25,P<0.05).The expression of CHST1 and its prognostic value were also confirmed with the data from GEO(all P<0.05).GSEA analysis found that high expression of CHST1 was related to the metastasis pathways such as ECM-receptor interaction,focal adhesion,and cell adhesion molecules(CAMs)(all P<0.05).Due to the close correlation between the immune microenvironment and tumor metastasis,this study further explored the regulation of CHST1 on immune microenvironment in STAD,and it was found that CHST1 was obviously related to the infiltration level of majority of immune cells.Especially,CHST1 high expression inhibited the infiltration of activated CD4+T cells but promoted the infiltration of M0 macrophages and activated mast cells(all P<0.05).Moreover,the expression of CHST1 was significantly correlated with related immune checkpoint genes of these immune cells(all P<0.05).Conclusion CHST1 was highly expressed in STAD,which was unfavorable to the patient’s prognosis,and it can be regarded as a promising molecular marker for STAD treatment.In addition,CHST1 might be involved in the invasion and metastasis of STAD by regulating the immune microenvironment.