p27(Kip1)is overexpressed in very early stages of hepatocarcinogenesis.
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 p27(Kip1) 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 p27(Kip1) expression in the majority of hepatocytes from normal and cirrhotic liver, whereas positive staining for p27(Kip1) protein was found in 75.0% and 93.8% of adenomatous hyperplasias and early HCC, respectively. The average p27(Kip1) 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 p27(Kip1) 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.
Yachida
Shinichi
S
Department of Surgery, Kagawa University, Kita-gun, Kagawa, Japan. syachida@kms.ac.jp
Sakamoto
Michiie
M
Imaida
Katsumi
K
Yokohira
Masanao
M
Saoo
Kousuke
K
Okano
Keiichi
K
Wakabayashi
Hisao
H
Maeta
Hajime
H
Suzuki
Yasuyuki
Y
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism
C436291:CDKN1B protein, human; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27