Article

p27(Kip1)is overexpressed in very early stages of hepatocarcinogenesis.

Department of Surgery, Kagawa University, Kita-gun, Kagawa, Japan.
Cancer Science (Impact Factor: 3.53). 10/2008; 99(11):2152-9. DOI: 10.1111/j.1349-7006.2008.00923.x
Source: PubMed

ABSTRACT 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.

0 Followers
 · 
86 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The so-called factor that binds to inducer of short transcripts-1 (FBI-1) purportedly plays an important role in tumorigenesis; however, its role in hepatocellular carcinoma (HCC) remains unknown. The objective of this study was to investigate the expression level, clinical relevance, and biologic function of FBI-1 in HCC. Real-time quantitative reverse transcriptase-polymerase chain reaction analysis, Western blot analysis, and immunohistochemical staining were used to detect expression levels of FBI-1 and to analyze its relation to clinicopathologic parameters and to the prognosis of patients with HCC. In addition, the biologic functions of FBI-1 in regulating cell proliferation, migration, and reaction to chemotherapy were detected by using HepG2 cells and SMMC-7721 cells; subsequently, the molecular mechanism of FBI-1 also was investigated. Finally, a xenograft mouse model was used to validate the observations obtained from in vitro studies. Expression levels of FBI-1 messenger RNA and protein were elevated significantly in HCC tissues compared with adjacent nontumorous liver tissues (ANLTs). Increased FBI-1 expression was correlated with multiple tumor nodes, Edmondson-Steiner grade, and a poor prognosis in patients with HCC (P < .05). In vitro studies revealed that FBI-1 was capable of promoting cell proliferation (but not cell migration) by regulating the cell cycle regulation proteins p53, p21, and p27. In addition, FBI-1 could inhibit cell death induced by 5-fluorouracil or doxorubicin through suppressing the activation of p53. Consistent with the in vitro data, FBI-1 was capable of promoting cell proliferation and enhancing chemotherapy resistance of HCC in vivo. The current findings indicated that FBI-1 plays an important role in HCC carcinogenesis and chemotherapy tolerance, and FBI-1 may served as a novel prognostic marker and therapeutic target for HCC.
    Cancer 01/2012; 118(1):134-46. DOI:10.1002/cncr.26251 · 4.90 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Non-alcoholic steatohepatitis (NASH) is a recently identified chronic liver disease, which progresses to liver cirrhosis and hepatocellular carcinoma (HCC). As the number of patients studied to date has been limited, clinically useful prognostic biomarkers of NASH-related HCC have not been available. In this study, we investigated the status of a cell-cycle regulator, p27, in NASH-related HCC. p27 has been regarded as a prognostic factor in various types of cancer patients. A total of 22 cases with NASH-related HCC were analyzed for p27 protein expression, and phosphorylation at threonine 157 (T157) and serine 10 (S10) by immunohistochemical analysis. The correlation of p27 with tumor characteristics, disease-free survival (DFS), and overall survival was analyzed. p27 expression was decreased in 13 HCCs (59%), and was significantly correlated with enlarged tumor size (p = 0.01) and increased cell proliferation (p < 0.01). Phospho-p27 at T157 and S10 was detected in four (18%) and seven (32%) cases, respectively, and patients positive for phospho-p27 (S10) showed reduced DFS (hazard ratio 7.623, p = 0.016) by univariate analysis. Further studies with more patients are required to verify the usefulness of p27 as a biomarker for predicting tumor recurrence in NASH patients.
    International Journal of Molecular Sciences 12/2013; 14(12):23499-515. DOI:10.3390/ijms141223499 · 2.34 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Radiofrequency ablation (RFA) is an effective standard local therapy for small hepatocellular carcinoma (HCC). However, local recurrence and/or tumor seeding after RFA remain as major problems. For better understanding of underlying factors, we clarified clinicopathologic features of recurrent HCCs treated with RFA. This retrospective study included 21 patients who underwent surgical resection for HCC disease recurrence after RFA. Clinicopathologic findings, including patterns of recurrence, immunohistochemical expression of proliferation markers (Ki-67 and p27Kip1) and survival outcome were assessed. The median time interval after RFA until the diagnosis of intrahepatic or/and extrahepatic tumor progression was 12 (range 3-84) months. Radical surgical resection was attempted for intrahepatic local recurrence in 16 patients (18 lesions), for peritoneal dissemination in 4, for lymph node metastases in 3 and for adrenal metastasis in 2. In 14 of the 21 (67%) patients, the recurrent HCCs were histologically diagnosed as of poorly differentiated type. Their average Ki-67 and p27Kip1 labeling indices were significantly higher (P = 0.020) and lower (P < 0.001), respectively, compared with values for the 108 HCCs surgically resected at the initial treatment. Portal involvement was significantly higher (P = 0.01) in recurrence tumors after RFA (72%) than in HCCs surgically resected at the initial treatment (43%). The mortality rate of salvage surgery was 0%, with cumulative survival rates 1 and 3 years of 58.9% and 35.7%, respectively. The recurrence tumors after RFA have characteristics of poor differentiation degree and abnormalities in cell cycle regulators and are associated with aggressive vascular invasiveness.
    Hepatology Research 08/2013; 44(11). DOI:10.1111/hepr.12223 · 2.22 Impact Factor

Preview

Download
2 Downloads