Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors without effective diagnostic biomarkers. This study intended to dynamically analyze serum proteomics in different pathological stages of liver diseases, and discover potential diagnostic biomarkers for early HCC. Patients with hepatitis B virus (HBV) infection, liver cirrhosis (LC), or HCC together with healthy controls (HC) were enrolled. Proteins differentially expressed between groups were screened using isobaric tagging for relative and absolute quantitation (iTRAQ), and promising HCC biomarker candidates were subjected to bioinformatics analysis, including K-means clustering, gene ontology (GO) and string network analysis. Potential biomarkers were validated by Western blotting and enzyme-linked immunosorbent assay (ELISA), and their diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis. Finally, 93 differentially expressed proteins were identified, of which 43 differed between HBV and HC, 70 between LC and HC, and 51 between HCC and HC. Expression levels of gelsolin (GELS) and sulfhydryl oxidase 1 (QSOX1) varied with disease state as follows: HC < HBV < LC < HCC. The reverse trend was observed with CD14. These iTRAQ results were confirmed by Western blotting and ELISA. Logistic regression and ROC curve analysis identified the optimal cut-off for alpha-fetoprotein (AFP), CD14 and AFP/CD14 was 191.4 ng/mL (AUC 0.646, 95%CI 0.467-0.825, sensitivity 31.6%, specificity 94.4%), 3.16 ng/mL (AUC 0.760, 95%CI 0.604-0.917, sensitivity 94.7%, specificity 50%) and 0.197 ng/mL (AUC 0.889, 95%CI 0.785-0.993, sensitivity 84.2%, specificity 83.3%) respectively. In conclusion, Assaying CD14 levels may complement AFP measurement for early detection of HCC.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, ranking sixth in morbidity and third in mortality worldwide [1, 2]
Proteins differentially expressed between groups were screened using isobaric tagging for relative and absolute quantitation, and promising HCC biomarker candidates were subjected to bioinformatics analysis, including K-means clustering, gene ontology (GO) and string network analysis
Numerous other candidate HCC biomarkers have been proposed, including lens culinaris agglutinin reactive AFP (AFP-L3), des-γ-carboxy prothrombin (DCP), prothrombin produced by vitamin K absence or antagonism II (PIVKA II), Golgi protein-73 (GP73), glypican-3 (GPC3), γ-glutamyl transferase (GGT), α-L-fucosidase (AFU), and alpha1-antitrypsin and apolipoprotein J (Apo-J) [4,5,6,7,8]
Summary
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, ranking sixth in morbidity and third in mortality worldwide [1, 2]. Early detection of HCC, such as through assay of serum biomarkers, is of tremendous importance. Serum alpha-fetoprotein (AFP), the most widely used biomarker for HCC diagnosis in the clinic, is less than satisfactory because of its low specificity and sensitivity [3]. Numerous other candidate HCC biomarkers have been proposed, including lens culinaris agglutinin reactive AFP (AFP-L3), des-γ-carboxy prothrombin (DCP), prothrombin produced by vitamin K absence or antagonism II (PIVKA II), Golgi protein-73 (GP73), glypican-3 (GPC3), γ-glutamyl transferase (GGT), α-L-fucosidase (AFU), and alpha1-antitrypsin and apolipoprotein J (Apo-J) [4,5,6,7,8]. Studies are needed to identify novel HCC biomarkers with superior early diagnostic potential
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