p27Kip1 is overexpressed in very early stages of hepatocarcinogenesis

Shinichi Yachida, Michiie Sakamoto, Katsumi Imaida, Masanao Yokohira, Kousuke Saoo, Keiichi Okano, Hisao Wakabayashi, Hajime Maeta, Yasuyuki Suzuki

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)


Hepatocellular carcinoma (HCC) associated with chronic liver disease evolves from precancerous lesions and early HCC to more malignant forms. Despite the demonstrated importance of cell-cycle regulators in tumor biology, there have been few studies of their role in multistep hepatocarcinogenesis. Expression of p27Kip1 and a degradation pathway associated protein, S-phase kinase-interacting protein 2 (Skp2), was therefore evaluated in surgically resected specimens of eight adenomatous hyperplasias, 16 early HCC and 126 classical HCC. Immunohistochemistry revealed no p27Kip1 expression in the majority of hepatocytes from normal and cirrhotic liver, whereas positive staining for p27Kip1 protein was found in 75.0% and 93.8% of adenomatous hyperplasias and early HCC, respectively. The average p27Kip1 labeling indices (LI) for adenomatous hyperplasias, early HCC, well differentiated HCC, moderately differentiated HCC and poorly differentiated HCC were 36.99, 43.59, 47.73, 49.24, and 30.21, respectively. Real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) analyses confirmed the increases. Skp2 LI were also significantly elevated in accordance with stepwise progression of hepatocarcinogenesis. Increased expression of Skp2 mRNA was observed most frequently in less differentiated tumors and Kaplan-Meier survival analysis showed a significantly association with a poor prognosis (P = 0.0496). In conclusion, a high level of p27Kip1 expression is evident from early stages of hepatocarcinogenesis, indicating that this parameter could be a useful diagnostic marker for precancerous lesions and early HCC. In addition, Skp2 expression correlates with tumor dedifferentiation and may contribute to biological aggression in HCC.

Original languageEnglish
Pages (from-to)2152-2159
Number of pages8
JournalCancer science
Issue number11
Publication statusPublished - 2008
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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