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Expression and Prognostic Roles of ß-Catenin in Hepatocellular Carcinoma

Correlation with Tumor Progression and Postoperative Survival

Department of Surgery, Institute of Clinical Medicine, University of Tsukuba, Ibaraki 305-8575, Japan [S. I., S. A., T. K., K. F.], and Departments of Pathology [M. I., M. H., J. S.] and Surgery [F. Y.], Ibaraki Prefectural Central Hospital and Cancer Center, Ibaraki 309-1793, Japan

Purpose: Although hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the human liver, the molecular changes and mechanisms that regulate its development and progression remain unclear. In the present study, we investigated the correlation between ß-catenin expression and clinical outcome in 51 patients with relatively small (maximal diameter < 30 mm), solitary HCCs.

Experimental Design: The tumors were classified according to histological tumor differentiation (grade I, 11 tumors; grade II, 28 tumors; grade III, 12 tumors). Using immunohistochemical methods to detect nuclear accumulation of ß-catenin, we investigated the correlation between ß-catenin expression and clinical outcome and compared the correlation with cyclin D1, Ki-67, and E-cadherin.

Results: Focal or generalized nuclear ß-catenin expression was observed in 36.4% (4 of 11) of the grade I tumors, 39.3% (11 of 28) of the grade II tumors, and 25% (3 of 12) of the grade III tumors. Nuclear ß-catenin-positive grade III tumors were associated with significantly poorer survival (P = 0.004), whereas none of the patients with nuclear ß-catenin-negative grade I tumors died. With regard to proliferative activity, positive nuclear ß-catenin staining correlated significantly with an increased Ki-67 labeling index in grade I (P < 0.0001) and grade III (P = 0.0045) tumors and with reduced epithelial cadherin expression in the cell membrane (P < 0.001). In contrast, no association with the expression of cyclin D1, one of the target factors of ß-catenin, was detected.

Conclusions: Our present data suggest that ß-catenin plays important roles in promoting tumor progression by stimulating tumor cell proliferation and reducing the activity of cell adhesion systems and is associated with a poor prognosis, especially in patients with poorly differentiated HCCs.

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