5-FU降低胃癌干细胞干性相关性研究

Study on the relatton in 5-FU reducing gastric cancer stem cell stemness

目的:探讨5-氟尿嘧啶(5-FU)对胃癌患者预后的影响以及与干细胞干性相关的分子机制。方法:对癌症和肿瘤基因图谱(TCGA)中包含完整临床信息(年龄、性别、TNM分期、组织学分级、生存时间、生存结局、5-FU化疗情况)和全基因组mRNA表达信息的258例胃癌患者进行5-FU化疗(n=64)和未化疗(n=194)患者的单因素和多因素生存分析;将干性标志物CD24、CD44、CD90(THY1)、CD133(PROM1)、CD166(ALCAM)、TFF2、EPCAM作为胃癌干性信号,利用基因集变异分析(GSVA)和基因集富集分析(GSEA)探索5-FU化疗和未化疗患者的胃癌干性差异以及对WNT、NOTCH、TGFβ、HEDGEHOG 4条干性相关信号通路的影响。结果:单因素生存分析显示,与未化疗患者相比,5-FU化疗能够显著提升胃癌患者的生存期(P=0.022),校正年龄、性别、TNM分期、组织学分级后,多因素生存分析差异仍然具有统计学意义(HR=0.43,95%CI:0.27~0.70,P<0.001);GSVA结果显示相对于未化疗患者,5-FU化疗能够显著降低胃癌患者的干性(P<0.01),GSEA结果显示5-FU化疗患者能够显著富集到干性降低的信号通路(ES=0.69,FDR=0.002);干性相关的4条信号通路中,5-FU化疗患者NOTCH信号通路的富集分数显著低于未化疗患者(P<0.01)。结论:5-FU化疗能够显著延长胃癌患者的生存期,可能与5-FU能够降低NOTCH信号通路的活性,从而降低胃癌的干性有关。

Objective-To investigate the effect of 5-fluorouracil(5-FU) on the prognosis of gastric cancer patients and the possible sternness related molecular mechanisms.Methods:The Cancer Genome Atlas(TCGA) includes 258 gastric cancer patients that contained complete clinical info rmation(age,sex,TNM staging,histological grading,survival time,survival outcomes,5-FU treatment) and whole genome mRNA expression information to perform univariate and multivariate survival analysis.Common sternness markers reported in the literature such as CD24,CD44,CD90(THYl),CD133(PROM1),CD166(Alcam),TFF2,EPCAM as a sternness signature for gastric cancer,using Gene Set Variation Analysis(GSVA) and Gene Set Enrichment Analysis(GSEA) explores the differences in the sternne ss of gastric cancer in patients with 5-FU chemotherapy and no-chemotherapy,as well as the effects on WNT,NOTCH,TGFβ and HEDGRHOG related signaling pathways.Results:Univariate survival analysis showed that compared with patients without chemotherapy,5-FU chemotherapy can significantly improve the survival period of gastric cancer patients,the difference is statistically significant(P=0.022).Correctio n of age,sex,TNM staging,histological cla s sification,multivariate survival analysis difference is still statistic ally significant(HR=0.4 3,95% CI(0.27,0.70),P<0.00 1).The results showed that 5-FU chemotherapy could significantly reduce the sternne ss(P<0.01) of patients with gastric cancer.GSVA and GSEA showed that patients with 5-FU chemotherapy could significantly be enriched to signaling pathways with reduced sternness(ES=0.69,FDR=0.002),and four signaling pathways related to sternne ss,the enrichment fraction of NOTCH signaling pathway in patients with 5-FU chemotherapy was significantly lower than that of patients without chemotherapy(P<0.01).Conclusion:5-FU chemotherapy has a good prognosis for gastric cancer patients,can significantly prolong the survival period of patients,may be related to 5-FU can reduce the activity of NOTCH signaling pathway,thus reduce the ste rnness of gastric cancer.