血浆长链非编码RNA HOTTIP与ROR联合高尔基体蛋白73对甲胎蛋白阴性肝癌的诊断与预后评估价值

Values of Golgi protein 73 combined with long non-coding RNA HOTTIP and ROR to the diagnosis and prognosis prediction of alpha-fetoprotein-negative hepatocellular carcinoma

目的探讨长链非编码RNA(long non-coding RNAs,lncRNAs)HOTTIP与ROR联合高尔基体蛋白73(Golgi protein 73,GP73)在甲胎蛋白(alpha-fetoprotein,AFP)阴性肝癌(AFP-negative hepatocellular carcinoma,AFP-NHCC)中的临床价值。方法 AFP-NHCC患者100例为AFP-NHCC组,肝脏良性疾病患者100例为肝脏良性疾病组,体检健康者110例为健康对照组。采用实时荧光定量PCR法检测3组血浆lncRNA HOTTIP、ROR,采用ELISA法检测3组血浆GP73,并进行组间比较;分析血浆lncRNA HOTTIP、ROR、GP73与AFP-NHCC临床特征的关系;绘制ROC曲线,分析血浆lncRNA HOTTIP、ROR与GP73对AFP-NHCC的诊断价值;多元logistic回归分析AFP-NHCC的危险因素。结果 AFP-NHCC组患者血浆lncRNA HOTTIP[12.8±0.6(-log)]、ROR表达[3.9±0.2(-log)]及GP73水平[(93.4±8.5)μg/L]高于肝脏良性疾病组[5.8±0.3(-log)、2.6±0.2(-log)、(30.8±3.7)μg/L]和健康对照组[5.7±0.2(-log)、2.5±0.2(-log)、(27.2±1.6)μg/L](P<0.05);血浆lncRNA HOTTIP、ROR和GP73表达水平与AFP-NHCC患者的淋巴结转移(HOTTIP:r=0.567,P=0.002;ROR:r=0.552,P=0.006;GP73:r=0.535,P=0.011)及TNM分级(HOTTIP:r=0.559,P=0.001;ROR:r=0.539,P=0.007;GP73:r=0.538,P=0.017)呈线性关联;ROC曲线分析显示,血浆GP73、lncRNA HOTTIP、ROR诊断AFP-NHCC的灵敏度/特异度分别为80.4%/76.9%、86.1%/74.5%和69.3%/63.2%,而联合三者诊断AFP-NHCC的特异度为92.9%;logistic回归多因素分析显示,在校正年龄、性别、吸烟史、饮酒史等因素影响后,血浆高GP73、lncRNA HOTTIP和ROR水平仍是AFP-NHCC发病的独立危险因素(OR=3.51,95%CI:1.53～5.72,P<0.001;OR=1.12,95%CI:1.03～1.34 P=0.032;OR=2.77,95%CI:1.47～5.08,P<0.001)。结论血浆lncRNA HOTTIP、ROR和GP73在AFP-NHCC的诊断以及评估AFP-NHCC患者发生肿瘤远处转移中有重要临床意义。

Objective To investigate the clinical value of Golgi protein 73（GP73）combined with long non-coding RNAs（lncRNAs） HOTTIP and ROR to the diagnosis and prognosis prediction of alpha-fetoprotein（AFP）-negative hepatocellular carcinoma（AFP-NHCC）.Methods Real-time quantitative PCR（RT-PCR）was used to detect the levels of plasma lncRNA HOTTIP and ROR,and ELISA was used to detect the levels of plasma GP73 in 100 patients with AFP-NHCC（cancer group）,100 patients with benign liver diseases（benign group）and 110 healthy volunteers（control group）.The relationships of plasma lncRNA HOTTIP,ROR and GP73 with clinical characteristics of AFP-NHCC were analyzed.ROC curve was drawn to analyze the diagnostic values of HOTTIP,ROR and GP73 to the diagnosis of AFP-NHCC.Multivariable logistic regression analysis was used to analyze the risk factors for AFP-NHCC.Results The levels of lncRNA HOTTIP,ROR and GP73 were significantly higher in cancer group（12.8±0.6（-log）,（3.9±0.2（-log）,（93.4±8.5）μg/L）than those in benign group（5.8±0.3（-log）,2.6±0.2（-log）,（30.8±3.7）μg/L）and control group（5.7±0.2（-log）,2.5±0.2（-log）,（27.2±1.6）μg/L）（P〈0.05）.The levels of lncRNA HOTTIP,ROR and GP73 were linearly correlated with lymph node metastasis（r=0.567,P=0.002;r=0.552,P=0.006;r=0.535,P=0.011）and TNM classification（r=0.559,P=0.001;r=0.539,P=0.007;r=0.538,P=0.017）in AFP-NHCC patients.ROC curve analysis showed that the sensitivities/specificities of GP73,lncRNA HOTTIP and ROR to AFP-NHCC were 80.4%/76.9%,86.1%/74.5% and 69.3%/63.2%,and the specificity of joint detection of them three was 92.9%.Logistic regression analysis showed that the high levels of GP73,lncRNA HOTTIP and ROR were the independent risk factors for AFP-NHCC after correcting age,sex,smoking and drinking history（OR=3.51,95%CI：1.53-5.72,P〈0.001;OR=1.12,95%CI：1.03-1.34,P=0.032;OR=2.77,95%CI：1.47-5.08,P〈0.001）.Conclusion The plasma GP73,lncRNA HOTTIP and ROR have great values to the diagnosis of AFP-NHCC and the evaluation of its remote metastasis.