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Expression and prognostic roles of the G1‐S modulators in hepatocellular carcinoma: p27 independently predicts the recurrence
Author(s) -
Ito Yasuhiro,
Matsuura Nariaki,
Sakon Masato,
Miyoshi Eiji,
Noda Katsuhisa,
Takeda Tsutomu,
Umeshita Koji,
Nagano Hiroyuki,
Nakamori Shoji,
Dono Keizo,
Tsujimoto Masahiko,
Nakahara Masaaki,
Nakao Kazuyasu,
Taniguchi Naoyuki,
Monden Morito
Publication year - 1999
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.510300114
Subject(s) - hepatocellular carcinoma , cyclin d1 , metastasis , cancer research , retinoblastoma , cell cycle , intrahepatic cholangiocarcinoma , cyclin , cyclin e , medicine , immunohistochemistry , clinical significance , pathology , cyclin b1 , biology , cancer , gene , cyclin dependent kinase 1 , biochemistry
Expression of cell‐cycle modulators at the G 1 ‐S boundary, retinoblastoma gene product (pRb), p21, p16, p27, p53, cyclin D 1 , and cyclin E was investigated with 104 hepatocellular carcinomas (HCC), as well as 90 of their adjacent noncancerous lesions and 9 normal liver control specimens. The labeling indices (LI) of pRb, p21, p16, and p27 were higher in HCC lesions than in the adjacent noncancerous lesions and normal controls. Especially, p27 LI in noncancerous lesions was significantly higher than that in normal livers ( P = .011). Aberrant p53 expression and cyclin D 1 and E overexpression were observed exclusively in HCC lesions. pRb was positive in 85.6% of the HCC cases and was not related to any clinicopathological parameters. The p21 LI was generally low (average, 5.5 ± 9.8). Although a negative regulator, p21 LI was higher in cases with intrahepatic metastasis ( P = .0359). The p16 LI was significantly decreased ( P = .0121) in cases with advanced stage. p27 LI was significantly decreased in cases with portal invasion ( P = .0409), poor differentiation ( P < .0001), larger size ( P = .0421), and intrahepatic metastasis ( P = .0878, borderline significance). On the other hand, aberrant p53 expression showed positive relationships with poor differentiation ( P = .0004) and Ki‐67 LI ( P = .0047). Cyclin D 1 overexpression was found in 32.6% of the cases and occurred more frequently in those with high Ki‐67 LI ( P = .0032), pRb expression ( P = .0202), poor differentiation ( P = .0612, borderline significance), and intrahepatic metastasis ( P = .0675, borderline significance). Cyclin E was overexpressed in 35.5% and had positive relationships with Ki‐67 LI ( P = .0269) and stage ( P = .0125). In univariate analysis, cases with p27 LI < 50 ( P = .0004), cyclin D 1 overexpression ( P = .0041), and cyclin E overexpression ( P = .0572, borderline significance) showed poorer outcomes for disease‐free survival (DFS). In multivariate analysis, p27 expression could be recognized as an independent prognostic marker for DFS. These findings suggest that in HCC: 1) p27 is active against HCC progression in early phases and, possibly, hepatocarcinogenesis as a negative regulator and can be a novel prognostic marker for DFS; and 2) cyclin D 1 predominantly works for cell‐cycle progression at the G 1 ‐S boundary