结直肠癌肝转移患者肠道菌群中肌苷单磷酸脱氢酶1的筛选及其临床意义

Screening of Inosine Monophosphate Dehydrogenase 1 in Intestinal Flora of Patients with Liver Metastasis from Colorectal Cancer and Its Clinical Significance

[目的]探讨肠道菌群及其相关代谢物肌苷单磷酸脱氢酶1(inosine monophosphate dehydrogenase 1,IMPDH1)在结直肠癌(colorectal cancer,CRC)肝转移中的临床意义。[方法]选取CRC非肝转移(CRCNLM)及肝转移(CRCLM)患者各9例。采用16S r DNA测序检测患者粪便,采用液质联用技术检测微生物样本中的代谢物,并筛选出与肝转移相关的Inosine 5′-Monophoshpate。分析TCGA数据库CRC资料中IMPDH1的表达及其对临床预后的影响。[结果]与CRCNLM比较,P.Sphingomonas、F.Bacillus、A.Skermanella等在CRCLM患者中明显升高。经非靶向代谢组学和Tax4Fun功能富集分析,Inosine 5′-Monophosphate等在肝转移组中升高,且Inosine 5′-Monophoshpate与F.Bacillus呈正相关(r=0.564,P<0.05)。IMPDH1是Inosine 5′-Monophoshpate的关键代谢酶,在CRC及其肝转移患者中显著升高。根据ROC曲线的cut-off值(16.4546)分为IMPDH1高低表达组,IMPDH1表达在CRC患者TNM分期组间差异具有统计学意义(P<0.05)。多因素结果显示,TNM分期(HR=1.041,95%CI:1.020~1.063)、IMPDH1表达(HR=1.007,95%CI:1.000~1.014)是影响CRC预后的独立风险因素(P<0.05)。随访11.69年后,IMPDH1高低表达患者的总生存率分别为15.2%和31.8%(P=0.01);随访6.86年后,在CRC肝转移患者中,IMPDH1高低表达患者的总生存率及1、3、5年生存率分别为0、59.2%、47.4%、0和12.3%、76.6%、58.5%、24.6%,差异有统计学意义(P=0.03)。[结论]F.Bacillus及其相关代谢物Inosine 5′-Monophoshpate的增加可能是导致CRC肝转移发生的原因之一,后者的关键酶IMPDH1高表达可能也是导致CRC预后差的风险因子。

[Objective]To explore the clinical significance of intestinal flora and its related metabolite inosine monophosphate dehydrogenase 1(IMPDH1)in liver metastasis of colorectal cancer(CRC).[Methods]The 16S rDNA sequencing and liquid mass spectrometry were applied to screen metabolites of intestinal flora in feces samples from 9 colorectal cancer patients with liver metastasis and 9 colorectal cancer patients without liver metastasis.The screening results showed that Inosine 5′-Monophosphate might be associated with liver metas-tasis in CRC patients.The data of IMPDH1 expression and its influence on clinical prognosis in CRC patients were obtained from TCGA database and analyzed.[Results]Compared with CRC patients without liver metas-tasis,the proportions of P.Sphingomonas,F.Bacillus,and A.Skermanella were significantly increased in CRC patients with liver metastasis.Tax4Fun function prediction and non-targeted metabolomics analysis showed that the IMPDH1 and other metabolites were increased in the CRC patients with liver metastasis,and IMPDH1 was positively correlated with the abundance of F.Bacillus(r=0.564,P<0.05).As a key metabolic enzyme of Inosine 5′-Monophosphate,MPDH1 was significantly elevated in CRC patients with liver metasta-sis.According to the cut-off value of ROC(16.4546),the CRC patients were divided into high and low expres-sion groups of IMPDH1.The expression levels of IMPDH1 were significantly associated with TNM stages of CRC patients(P<0.05).Multivariate regression results showed that TNM stage(HR=1.041,95%CI:1.020~1.063)and IMPDH1(HR=1.007,95%CI:1.000~1.014)were independent risk factors for the prognosis of CRC patients(P<0.05).After 11.69-year follow-up,the survival of CRC patients with high and low expression of IMPDH1 were 15.2%and 31.8%,respectively(P=0.01).Follow-up for 6.86-year,the overall,1,3,5-survival of liver metastasis patients with high and low expression of IMPDH1 were 0,59.2%,47.4%,0 and 12.3%,76.6%,58.5%,24.6%,respectively(P=0.03).[Conclusion]The increase of F.Bacillus abundance and its related metabolite Inosine 5′-Monophosphate may be associated with liver metastasis of CRC patients.The high expression of IMPDH1(a key metabolic enzyme of Inosine 5′-Monophosphate)may be a risk factor for poor prognosis of CRC patients.