N-myc下游调控基因家族在肝细胞癌中的诊断及预后价值

Value of the NDRG family in the diagnosis and prognostic evaluation of hepatocellular carcinoma

目的基于生物信息挖掘技术,分析N-myc下游调控基因(NDRG)家族在肝细胞癌(HCC)患者组织中的表达情况及与病理特征和预后的相关性。方法利用ONCOMINE、GEPIA和Kaplan-Meier Plotter挖掘了HCC患者的NDRG表达和生存数据。共收集419例HCC组织的基因表达数据分析NDRG家族表达差异,将其分为肝癌组(n=369)和正常肝组织组(n=50)。生存分析共收集364例HCC组织的NDRG家族基因表达数据,分为低表达组[NDRG1(212例)、NDRG2(185例)、NDRG3(182例)、NDRG4(184例)]和高表达组[NDRG1(152例)、NDRG2(179例)、NDRG3(182例)、NDRG4(180例)]。计量资料两组间比较采用t检验,多组间比较采用单因素方差分析,进一步比较采用Dunnett-t检验;生存分析采用log-rank检验。结果HCC组织中NDRG1/3的表达水平高于正常肝组织,而NDRG2在癌组织中的表达水平低于正常肝组织(P值均<0.05)。不同病理分期NDRG1/2/3/4表达差异组间比较差异均有统计学意义(F值分别为3.67、2.97、5.51、3.56,P值均<0.05)。生存分析表明,NDRG1/3高转录组与低转录组相比,总生存期(OS)[NDRG1:风险比(HR)=1.75,95%可信区间(95%CI):1.24~2.47,P<0.05;NDRG3:HR=1.83,95%CI:1.28~2.60,P<0.05]和无进展生存期(PFS)(NDRG1:HR=1.39,95%CI:1.03~1.87,P<0.05;NDRG3:HR=1.71,95%CI:1.27~2.30,P<0.05)均显著缩短。NDRG2低转录组和高转录组相比,OS(HR=0.43,95%CI:0.30~0.62,P<0.05)和PFS(HR=0.59,95%CI:0.44~0.80,P<0.05)均显著缩短。NDRG4高低转录组间OS差异无统计学意义(HR=1.4,95%CI:0.99~1.98,P>0.05),高转录组和低转录组相比PFS显著延长(HR=0.53,95%CI:0.39~0.72,P<0.05)。结论NDRG1/3的高表达和NDRG2的低表达可能与HCC进展相关,提示HCC患者预后不良。

Objective To investigate the expression of the N-myc downstream regulated gene(NDRG)family in hepatocellular carcinoma(HCC)and its association with pathological features and prognosis based on bioinformatics mining.Methods The expression of the NDRG family and the survival data of patients with HCC were obtained using ONCOMINE,GEPIA,and Kaplan-Meier Plotter.The gene expression data of the NDRG family were obtained from 419 HCC tissue samples,which were divided into liver cancer group with 369 samples and normal liver tissue group with 50 samples.Survival data were collected from 364 HCC tissue samples,which were divided into low expression groups(NDRG1 group with 212 samples,NDRG2 group with 185 samples,NDRG3 group with 182 samples,and NDRG4 group with 184 samples)and high expression groups(NDRG1 group with 152 samples,NDRG2 group with 179 samples,NDRG3 group with 182 samples,and NDRG4 group with 180 samples).The t-test was used for comparison of continuous data between two groups,a one-way analysis of variance was used for comparison between multiple groups,and then the Dunnett-t test was performed;the log-rank test were used for survival analysis.Results The expression of NDRG1 and NDRG3 in HCC tissue was higher than that in normal liver tissue,while the expression of NDRG2 in cancer tissue was lower than that in normal liver tissue(all P<0.05).There were significant differences in the expression of NDRG1,NDRG2,NDRG3,and NDRG4 between the patients with different pathological stages(F=3.67,2.97,5.51,and 3.56,all P<0.05).The survival analysis showed that compared with the group with low transcription of NDRG1 and NDRG3,the group with high transcription of NDRG1 and NDRG3 had significantly shortened overall survival(OS)(NDRG1:hazard ratio[HR]=1.75,95%confidence interval[CI]:1.24-2.47,P<0.05;NDRG3:HR=1.83,95%CI:1.28-2.60,P<0.05)and progression-free survival(PFS)(NDRG1:HR=1.39,95%CI:1.03-1.87,P<0.05;NDRG3:HR=1.71,95%CI:1.27-2.30,P<0.05).Compared with the group with low transcription of NDRG2,the group with high transcription of NDRG2 had significantly shortened OS(HR=0.43,95%CI:0.30-0.62,P<0.05)and PFS(HR=0.59,95%CI:0.44-0.80,P<0.05).There was no significant difference in OS between the group with high transcription of NDRG4 and the group with low transcription of NDRG4(HR=1.4,95%CI:0.99-1.98,P>0.05),and compared with the group with low transcription of NDRG4,the group with high transcription of NDRG4 had significantly prolonged PFS(HR=0.53,95%CI:0.39-0.72,P<0.05).Conclusion The high expression of NDRG1 and NDRG3 and the low expression of NDRG2 may be associated the progression of HCC and suggest the poor prognosis of HCC patients.