Proteomic mining in the dysplastic liver of WHV/c-myc mice - insights and indicators for early hepatocarcinogenesis

Because of the asymptomatic process of carcinogenesis, the early detection of cancers such as hepatocellular carcinoma (HCC) is very challenging. Tumor-prone transgenic mouse models of oncogenesis can provide a stable and powerful tool for the analysis of cancer initiation, and are therefore promising for the discovery of early putative biomarkers of HCC. Using a label-free proteomic quantification strategy, we comprehensively investigated the protein expression profile in the livers of three 2-month-old WHV/c-myc mice at the dysplastic stage, with age-matched wt-C57 mice as controls. We identified 2781 proteins, 540 of which were differentially expressed. These proteins successfully characterized certain precancerous biological processes and alterations in transcriptional regulators before tumor onset. Two candidates, FK506-binding protein 4 (FKBP52) and ferritin heavy chain, were taken as examples for a search from the mouse model to clinical human tissues. Their levels in serum samples were determined by western blotting, and showed a noteworthy ability to distinguish between HCC and control cases. Immunohistochemical analysis with tissue microarrays confirmed the differential expression of FKBP52 between HCC and the paired controls (P < 0.001). The regulation of FKBP52 was also discovered to be relevant to HCC staging, with a dramatic decline at stage III (P < 0.05). The potentials of the candidate pool in this study were discussed in terms of delineating c-myc-induced hepatocarcinogenesis and facilitating biomarker discovery for early HCC diagnosis.