Reduced Expression of Adherens Junctions Associated Protein 1 Predicts Recurrence of Hepatocellular Carcinoma After Curative Hepatectomy

Background. Hepatocellular carcinoma (HCC) frequently recurs after curative resection. Therefore, the availability of sensitive biomarkers for progression and recurrence is essential for managing patients' clinical course. Adherens junctions associated protein 1 (AJAP1) may serve this purpose, because it mediates activities of tumor cells. Methods. AJAP1 mRNA levels and those of genes encoding potential interacting proteins, such as SRC in HCC cell lines, and 144 pairs of resected liver tissues were determined as well as the methylation status of the AJAP1 promoter and copy number changes at AJAP1 locus. The expression pattern of AJAP1 protein was evaluated using immunohistochemistry. Results. AJAP1 mRNA levels varied among nine HCC cell lines, and AJAP1 expression was reactivated after demethylation of its promoter. AJAP1 mRNA levels correlated inversely with those of SRC in HCC cell lines and tissues. AJAP1 mRNA levels were suppressed in HCC tissues. The expression pattern of AJAP1 correlated significantly with that of AJAP1 mRNA. Low levels of AJAP1 mRNA in patients with HCC associated significantly with elevated levels of tumor markers, larger tumor size, serosal infiltration, vascular invasion, hypermethylation of the AJAP1 promoter, and copy number loss at AJAP1 locus. Patients with low levels of AJAP1 expression were more likely to experience shorter disease-free survival (DFS), and multivariate analysis identified low AJAP1 expression as an independent factor for predicting DFS. Conclusions. AJAP1 may function as a key regulatory molecule associated with the recurrence of HCC. Hypermethylation of the AJAP1 promoter is a key regulatory mechanism controlling AJAP1 expression.