Yachida S, Sakamoto M, Imaida K, et al. p27(Kip1) is overexpressed in very early stages of hepatocarcinogenesis

Department of Surgery, Kagawa University, Kita-gun, Kagawa, Japan.
Cancer Science (Impact Factor: 3.52). 10/2008; 99(11):2152-9. DOI: 10.1111/j.1349-7006.2008.00923.x
Source: PubMed


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.

Full-text preview

Available from:
  • Source
    • "Meanwhile, hepatocarcinogenesis is a long-term, multistep process associated with changes in gene expression profiles. In the last several years, there have been important gains in our understanding of the pathogenesis of HCC and our appreciation of the critical oncogenic and tumor suppressor pathways involved in hepatocarcinogenesis [1-5]. Despite this, current knowledge about the molecular pathogenesis of HCC is a result of investigations of fully developed HCC. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Liver cancer is a heterogeneous disease in terms of etiology, biologic and clinical behavior. Very little is known about how many genes concur at the molecular level of tumor development, progression and aggressiveness. To explore the key genes involved in the development of liver cancer, we established a rat model induced by diethylnitrosamine to investigate the gene expression profiles of liver tissues during the transition to cirrhosis and carcinoma. A rat model of liver cancer induced by diethylnitrosamine was established. The cirrhotic tissue, the dysplasia nodules, the early cancerous nodules and the cancerous nodules from the rats with lung metastasis were chosen to compare with liver tissue of normal rats to investigate the differential expression genes between them. Affymetrix GeneChip Rat 230 2.0 arrays were used throughout. The real-time quantity PCR was used to verify the expression of some differential expression genes in tissues. The pathological changes that occurred in the livers of diethylnitrosamine-treated rats included non-specific injury, fibrosis and cirrhosis, dysplastic nodules, early cancerous nodules and metastasis. There are 349 upregulated and 345 downregulated genes sharing among the above chosen tissues when compared with liver tissue of normal rats. The deregulated genes play various roles in diverse processes such as metabolism, transport, cell proliferation, apoptosis, cell adhesion, angiogenesis and so on. Among which, 41 upregulated and 27 downregulated genes are associated with inflammatory response, immune response and oxidative stress. Twenty-four genes associated with glutathione metabolism majorly participating oxidative stress were deregulated in the development of liver cancer. There were 19 members belong to CYP450 family downregulated, except CYP2C40 upregulated. In this study, we provide the global gene expression profiles during the development and progression of liver cancer in rats. The data obtained from the gene expression profiles will allow us to acquire insights into the molecular mechanisms of hepatocarcinogenesis and identify specific genes (or gene products) that can be used for early molecular diagnosis, risk analysis, prognosis prediction, and development of new therapies.
    Full-text · Article · Aug 2009 · Journal of Experimental & Clinical Cancer Research
  • [Show abstract] [Hide abstract]
    ABSTRACT: In intrahepatic cholangiocarcinomas (ICCs), the prognostic significance of p27(Kip1), a cyclin-dependent kinase inhibitor, remains controversial, and there have been no studies of degradation pathway associated proteins, S-phase kinase-interacting protein (Skp2), and Jun activation domain-binding protein-1 (Jab1). In the present study of 74 patients with ICC-mass forming type (ICC-MF) undergoing radical surgery, we determined immunohistochemical expression of p27(Kip1), Skp2, and Jab1 and examined relationships with clinicopathologic findings and patient survival. On the basis of the average of labeling indices, we set cutoff values to define high and low expressors and divided the cases into two groups. A statistically significant correlation was found between low p27(Kip1) expression and lymph node metastasis (P = .009). Patient survival in the low p27(Kip1) expression group (n = 25) was also significantly worse than that in the high p27(Kip1) expression group (n = 49, P = .0007). A significant inverse correlation was found between p27(Kip1) and Skp2 expression (P = .016). High Skp2 expression (n = 36) was significantly associated with poor prognosis (P = .0046). High Jab1 expression was observed in 32 cases, but there was no statistically significant relationship with clinicopathologic findings or patient survival. The multivariate analysis revealed that low p27(Kip1) and high Skp2 expression are independent and significant factors of poor prognosis. The results suggest that low p27(Kip1) and high Skp2 expression are associated with aggressive tumor behavior, and these cell-cycle regulators are useful markers to predict outcome of patients with ICC-MF.
    No preview · Article · Dec 2008 · Annals of Surgical Oncology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Molecular diagnostics is one of the major growth areas of modern medicine, with real-time PCR established as a qualitative and quantitative technology that is rapid, accurate and sensitive. The sequencing of the human genome, comprehensive genomic, mRNA and miRNA expression profiling of numerous cancer types, the ongoing identification of disease-associated polymorphisms and the expanding availability of genomic sequence information for human pathogens has opened the door to a wide range of translational applications for this technology. Consequently, novel real-time PCR assays have been developed for diagnosis and prognosis, treatment monitoring, transplant biology and pathogen detection, as well as more controversial uses such as lifestyle genotyping. However, this technology is still troubled by significant technical deficiencies. Hence its often-improper use as a clinical tool has important public health implications, most recently demonstrated through its association with the measles, mumps and rubella vaccine/autism controversy. This serves as a timely reminder of the indispensable requirement for careful experimental design, validation and analysis.
    Full-text · Article · Apr 2009 · Expert Review of Molecular Diagnostics
Show more