Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is a worldwide prevalent and deadly neoplasia, which occurs almost in the background of cirrhotic liver as a result of chronical hepatitis virus infection
The establishment of isobaric tags for relative and absolute quantitation and two-dimensional liquid chromatography−tandem mass spectrometry (2D LC−MS/MS) for large-scale analysis of protein expression is a new tool for markers, which has not been used in the multistage hepatocarcinomagenisis. iTRAQ 2D LC−MS/MS has made it possible to seek novel molecular markers in more large-scale proteomics for diagnosis, outcome prediction, and identifying molecules involved in carcinogenesis in a process of tumor development
hepatitis liver (HL) and hepatocellular carcinoma (HCC) groups had similar proteomic patterns and comprised a major sample cluster, cirrhotic liver (CL) added to this group yielded another cluster
Summary
Hepatocellular carcinoma (HCC) is a worldwide prevalent and deadly neoplasia, which occurs almost in the background of cirrhotic liver as a result of chronical hepatitis virus infection. It has been reported that 15–20% of chronic hepatitis B patients progress to cirrhosis within 5 years and that the annual incidence of HCC is 2.8% [3]. Hepatocarcinogenesis is a typical multistage process characterized by chronic viral infection, liver cirrhosis, and HCC [4, 5]. The most protein markers of HCC arise from the various established methods, including indirect gene expression analysis (gene arrays) and direct proteomics [12]. The establishment of isobaric tags for relative and absolute quantitation (iTRAQ) and two-dimensional liquid chromatography−tandem mass spectrometry (2D LC−MS/MS) for large-scale analysis of protein expression is a new tool for markers, which has not been used in the multistage hepatocarcinomagenisis. The establishment of isobaric tags for relative and absolute quantitation (iTRAQ) and two-dimensional liquid chromatography−tandem mass spectrometry (2D LC−MS/MS) for large-scale analysis of protein expression is a new tool for markers, which has not been used in the multistage hepatocarcinomagenisis. iTRAQ 2D LC−MS/MS has made it possible to seek novel molecular markers in more large-scale proteomics for diagnosis, outcome prediction, and identifying molecules involved in carcinogenesis in a process of tumor development
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