Background: As is known for many types of human cancers, the hepatocellular carcinoma (HCC) associated with chronic liver disease shows an obvious multistage process of tumor progression. Despite the demonstrated importance of cell-cycle regulators in tumor biology, there have only been a few studies of their role in multistep hepatocarcinogenesis. Recently, we reported that a high level of p27(Kip1) expression is evident from the very early stages of hepatocarcinogenesis.
Methods: In the present study, expression of p27(Kip1) and Jun activation domain binding protein-1 (Jab1), which is a key molecule involved in posttranslational regulation of p27(Kip1), was evaluated in surgically resected specimens of 8 dysplastic nodules (DNs), 16 early HCCs, and 126 classical HCCs.
Results: Immunohistochemistry revealed no Jab1 expression in the majority of hepatocytes in noncancerous normal liver tissue and cases of chronic hepatitis or cirrhosis. In contrast, Jab1 was overexpressed in 50% (4/8) and 50% (8/16) of DNs and early HCCs, respectively, and the labeling index was increased in line with the degree of loss of differentiation in classical HCCs. Real-time quantitative reverse transcription polymerase chain reactions revealed the Jab1 mRNA levels in all tested early and well-differentiated HCCs to be increased compared with matched nontumorous liver specimens. The Spearman coefficient pointed to a high correlation between p27(Kip1) and Jab1 mRNA expression levels (P = 0.0014).
Conclusions: Jab1 expression, as well as p27(Kip1) upregulation, is evident from the very early stages of hepatocarcinogenesis, suggesting that Jab1 could be a diagnostic marker and a treatment target for precancerous lesions and early HCCs.