Xu Xiao, Liu Zhikun, Wang Jianguo, Xie Haiyang, Li Jie, Cao Jili, Zhou Lin, Zheng Shusen
Division of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.
Oncotarget. 2016 Mar 22;7(12):13730-41. doi: 10.18632/oncotarget.7316.
The more accurate biomarkers have long been desired for hepatocellular carcinoma (HCC). Here, we characterized global large-scale proteomics of multistep hepatocarcinogenesis in an attempt to identify novel biomarkers for HCC. Quantitative data of 37874 sequences and 3017 proteins during hepatocarcinogenesis were obtained in cohort 1 of 75 samples (5 pooled groups: normal livers, hepatitis livers, cirrhotic livers, peritumoral livers, and HCC tissues) by iTRAQ 2D LC-MS/MS. The diagnostic performance of the top six most upregulated proteins in HCC group and HSP70 as reference were subsequently validated in cohort 2 of 114 samples (hepatocarcinogenesis from normal livers to HCC) using immunohistochemistry. Of seven candidate protein markers, PARP1, GS and NDRG1 showed the optimal diagnostic performance for HCC. PARP1, as a novel marker, showed comparable diagnostic performance to that of classic markers GS and NDRG1 in HCC (AUCs = 0.872, 0.856 and 0.792, respectively). A significant higher AUC of 0.945 was achieved when three markers combined. For diagnosis of HCC, the sensitivity and specificity were 88.2% and 81.0% when at least two of the markers were positive. Similar diagnostic values of PARP1, GS and NDRG1 were confirmed by immunohistochemistry in cohort 3 of 180 HCC patients. Further analysis indicated that PARP1 and NDRG1 were associated with some clinicopathological features, and the independent prognostic factors for HCC patients. Overall, global large-scale proteomics on spectrum of multistep hepatocarcinogenesis are obtained. PARP1 is a novel promising diagnostic/prognostic marker for HCC, and the three-marker panel (PARP1, GS and NDRG1) with excellent diagnostic performance for HCC was established.
长期以来，人们一直渴望获得更准确的肝细胞癌（HCC）生物标志物。在此，我们对多步骤肝癌发生过程进行了全球大规模蛋白质组学分析，试图鉴定出HCC的新型生物标志物。通过iTRAQ 2D LC-MS/MS在75个样本的队列1（5个合并组：正常肝脏、肝炎肝脏、肝硬化肝脏、癌旁肝脏和HCC组织）中获得了肝癌发生过程中37874个序列和3017种蛋白质的定量数据。随后，使用免疫组织化学在114个样本的队列2（从正常肝脏到HCC的肝癌发生过程）中验证了HCC组中上调最明显的六种蛋白质以及作为对照的HSP70的诊断性能。在七种候选蛋白质标志物中，PARP1、GS和NDRG1对HCC表现出最佳的诊断性能。PARP1作为一种新型标志物，在HCC中的诊断性能与经典标志物GS和NDRG1相当（AUC分别为0.872、0.856和0.792）。当三种标志物联合使用时，AUC显著提高至0.945。对于HCC的诊断，当至少两种标志物呈阳性时，敏感性和特异性分别为88.2%和81.0%。在180例HCC患者的队列3中，通过免疫组织化学证实了PARP1、GS和NDRG1具有相似的诊断价值。进一步分析表明，PARP1和NDRG1与一些临床病理特征相关，并且是HCC患者的独立预后因素。总体而言，获得了多步骤肝癌发生谱的全球大规模蛋白质组学数据。PARP1是一种新型且有前景的HCC诊断/预后标志物，并且建立了对HCC具有优异诊断性能的三标志物组合（PARP1、GS和NDRG1）。
