CPT1A、CPT2表达水平在肾透明细胞癌预后评估中的价值

Predictive value of CPT1A and CPT2 expression levels in prognosis of clear cell renal cell carcinoma

目的探索脂肪酸降解相关基因肉碱棕榈酰转移酶IA(carnitine Palmitoyltransferase 1A,CPT1A)和肉碱棕榈酰转移酶Ⅱ(carnitine Palmitoyltransferase 2,CPT2)在肾透明细胞癌(clear cell renal cell carcinoma,ccRCC)的表达及意义。方法生物信息学分析癌症基因组图谱(The Cancer Genome Atlas,TCGA)、纪念斯隆·凯特琳癌症中心(Memorial Sloan Kettering Cancer Center,MSKCC)的ccRCC数据中脂肪酸降解相关基因及代谢物。采用免疫组化染色和Western blot分析脂肪酸降解关键基因CPT1A、CPT2蛋白表达水平。构建ccRCC组织芯片(n=103),通过CPT1A、CPT2免疫组化染色评分分析二者表达和预后的关系。构建并初步评价预后预测模型。结果生物信息学分析结果显示,CPT1A、CPT2是参与棕榈酰肉碱代谢、脂肪酸氧化及肾癌进展的关键基因。组织芯片和TCGA队列的结果显示:(1)ccRCC中CPT1A和CPT2的表达水平均较正常肾组织降低(P<0.05);(2)免疫组化评分显示CPT1A、CPT2的表达与病理分级(r=-0.243,P=0.013;r=-0.391,P<0.01)和TNM分期(r=-0.363,P<0.01;r=-0.430,P<0.01)负相关;(3)CPT1A、CPT2低表达与较低的无疾病生存率相关(P<0.01)。Cox回归分析结果显示,CPT2表达水平是ccRCC独立预后因素(P<0.01)。TNM-CPT1A、TNM-CPT2预后模型能显著提高TNM分期对预后的预测能力。结论与高表达患者相比,CPT1A、CPT2低表达预示ccRCC患者预后不良。

Objective To explore the expressions of fatty acid degradation related genes carnitine palmitoyltransferase 1A(CPT1A)and carnitine palmitoyltransferase 2(CPT2)in clear cell renal cell carcinoma(ccRCC)and their prognostic significance.Methods The genes involved in fatty acid degradation and their related metabolites in the ccRCC datasets from The Cancer Genome Atlas(TCGA)and Memorial Sloan Kettering Cancer Center(MSKCC)were analyzed by bioinformatic tools.Clinical data of renal carcinoma patients admitted to our hospital from 2007 to 2016 were collected.Immunohistochemical(IHC)staining and Western blotting were performed to detect the levels of CPT1A and CPT2,key genes of fatty acid degradation.The tissue chips of ccRCC were prepared(n=103),and IHC scores of CPT1A and CPT2 were used to estimate the relationship between their expression and prognosis of patients.Subsequently,the prognostic models were constructed and preliminarily evaluated.Results Bioinformatics analysis revealed that CPT1A and CPT2 were key genes involved in palmitylcarnitine metabolism,fatty acid oxidation and renal carcinoma progression.The results of tissue microarray and TCGA cohort showed that(1)The expression levels of both CPT1A and CPT2 in ccRCC were lower than those in normal renal tissues(P<0.05);(2)IHC scores indicated that the expression levels of CPT1A and CPT2 were negatively correlated with pathological grade(r=-0.243,P=0.013;r=-0.391,P<0.01)as well as with TNM stage(r=-0.363,P<0.01;r=-0.430,P<0.01);(3)Reduced levels of CPT1A and CPT2 were associated with declined disease-free survival(P<0.01).Moreover,Cox regression analysis showed that CPT2 expression level was an independent prognostic factor for ccRCC patients(P<0.01).Finally,TNM-CPT1A and TNM-CPT2 models significantly improved the ability of TNM stage alone to predict ccRCC prognosis.Conclusion Compared with patients with high expression,low expression of CPT1A and CPT2 predicted poor prognosis in patients with ccRCC.