Expression and prognostic roles of beta-catenin in hepatocellular carcinoma: correlation with tumor progression and postoperative survival.
OBJECTIVE
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 beta-catenin expression and clinical outcome in 51 patients with relatively small (maximal diameter < 30 mm), solitary HCCs.


METHODS
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 beta-catenin, we investigated the correlation between beta-catenin expression and clinical outcome and compared the correlation with cyclin D1, Ki-67, and E-cadherin.


RESULTS
Focal or generalized nuclear beta-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 beta-catenin-positive grade III tumors were associated with significantly poorer survival (P = 0.004), whereas none of the patients with nuclear beta-catenin-negative grade I tumors died. With regard to proliferative activity, positive nuclear beta-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 beta-catenin, was detected.


CONCLUSIONS
Our present data suggest that beta-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.
Inagawa
Satoshi
S
Department of Surgery, Institute of Clinical Medicine, University of Tsukuba, Ibaraki 305-8575, Japan. inagawa@tmch.or.jp
Itabashi
Masayuki
M
Adachi
Shinya
S
Kawamoto
Toru
T
Hori
Masao
M
Shimazaki
Jiro
J
Yoshimi
Fuyo
F
Fukao
Katashi
K
D000368:Aged; D015820:Cadherins / Q000096:biosynthesis; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis* / Q000378:metabolism* / Q000401:mortality; D002448:Cell Adhesion; D002454:Cell Differentiation; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism; D019938:Cyclin D1 / Q000096:biosynthesis; D003598:Cytoskeletal Proteins / Q000096:biosynthesis*; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008113:Liver Neoplasms / Q000175:diagnosis* / Q000378:metabolism* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D013997:Time Factors; D015534:Trans-Activators; D051176:beta Catenin
C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; D019394:Ki-67 Antigen; D015534:Trans-Activators; D051176:beta Catenin; D019938:Cyclin D1