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Naohito Uchida

Publications and source records attributed to Naohito Uchida.

At least 19 recordsLinked to original sources
PubMed2007

Identification of c-Yes expression in the nuclei of hepatocellular carcinoma cells: involvement in the early stages of hepatocarcinogenesis.

It is thought that the subcellular distribution of Src-family tyrosine kinases, including c-Yes binding to the cellular membrane, is membranous and/or cytoplasmic. c-Yes protein tyrosine kinase is known to be related to malignant transformation. However, the expression patterns of c-Yes in hepatocellular carcinoma (HCC) remains unknown. In the present study, we report that c-Yes is expressed not only in the membrane and cytoplasm, but also in the nuclei of cancer cells in some human HCC tissues and in a human HCC cell line. We examined the expression and localization of c-Yes in human HCC cell lines (HLE, HLF, PLC/PRF/5 and Hep 3B) by Western blotting and immunohistochemical analyses; we also examined the expression of c-Yes by immunohistochemistry and Western blotting in the tissues of various liver diseases, including 39 samples from HCC patients. We used an antibody array to detect proteins that bind to nuclear c-Yes in PLC/PRF/5 cell line. c-Yes was found to be expressed in the membranes and cytoplasm of HLE, HLF and Hep 3B HCC cells; it was also detected in the nuclei in addition to the membranes and cytoplasm of PLC/PRF/5 HCC cells. HCC with nuclear c-Yes was detected in 5 of 39 cases (13.0%), and nuclear c-Yes expression was not detected in normal, chronic hepatitis or cirrhotic livers. All HCCs with nuclear c-Yes expression were well-differentiated, small tumors at the early stages. In the PLC/PRF/5 cell line, the nuclear localization of c-Yes with cyclin-dependent kinase 1 was confirmed by a protein antibody array. In conclusion, nuclear c-Yes expression was found in cancer cells at the early stages of hepatocarcinogenesis, suggesting that nucleus-located c-Yes may be a useful marker to detect early-stage HCC.

Adult↗
PubMed2007

Sequential assessment of the intrahepatic expression of epidermal growth factor and transforming growth factor-beta1 in hepatofibrogenesis of a rat cirrhosis model.

Responses of the liver to chronic injury include inflammation, regeneration and fibrosis, which finally lead to cirrhosis. The cause of liver cirrhosis appears to be impaired proliferative capability of hepatocytes caused by continuous hepatic damage, and subsequent accumulation of extracellular matrix produced by hepatic stellate cells (HSCs). Epidermal growth factor (EGF) and transforming growth factor-beta1 (TGF-beta1) play a crucial role in hepatocyte proliferation and hepatofibrogenesis, respectively. However, sequential analyses of the intrahepatic expression of EGF and TGF-beta1 in the course of cirrhosis development have not been examined fully. In the present study, liver cirrhosis was produced in rats by intraperitoneal administration of dimethylnitrosamine (DMN), and intrahepatic mRNA expression levels of proliferating cell nuclear antigen (PCNA), EGF and TGF-beta1 were quantitatively estimated by a real-time reverse transcription-polymerase chain reaction method. Histological and semiquantitative densitometric examination of liver sections revealed that the accumulation of extracellular matrix components was increased according to the period of DMN treatment. Histological examination of liver sections of rats treated with DMN for 4 and 6 weeks revealed pre-cirrhosis and cirrhosis, respectively. Intrahepatic mRNA expression levels of PCNA and EGF correlated well. Expression levels of both molecules were increased significantly during the course of cirrhosis development, but decreased significantly at the time of complete cirrhosis manifestation. In contrast, intrahepatic TGF-beta1 expression was increased significantly according to the period of DMN treatment, and reached a peak at the time of cirrhosis manifestation. These results suggest that proliferative capability of hepatocytes was impaired by continuous liver damage due, in part, to the decrease of a hepatocyte mitogen EGF, and that increased intrahepatic TGF-beta1 activated HSCs to retrieve space lost by hepatocyte destruction, resulting in complete cirrhosis manifestation.

Animals↗
PubMed2006

Further resolution of alpha-fetoprotein glycoforms by two-dimensional isoelectric focusing and lectin affinity electrophoresis.

Human alpha-fetoprotein (AFP) from serum of patients with cirrhosis and hepatocellular carcinoma (HCC) was separated into several bands by IEF and by erythroagglutinating phytohemagglutinin (E-PHA) affinity electrophoresis. These AFP bands were directly compared in 2-D IEF and E-PHA affinity electrophoresis. IEF of serum AFP was run in 1% agarose IEF gel with 3% Pharmalyte 4.5-5.4. After IEF, a part of the gel was stained for AFP and another part of the gel corresponding to the area of separated AFP bands was cut in 1 mm x 39 mm along the focused direction and transferred to a trough in 1% agarose gel with 0.3 mg/mL E(4)-PHA for second-dimensional affinity electrophoresis. Separated 2-D AFP spots were visualized by antibody-affinity blotting and identified by combining the systems of Johnson et al.. (Johnson, P. J., Ho, S., Cheng, P., Chan, A. et al.., Cancer 1995, 75, 1663-1668) for AFP-I-+IV and of Taketa et al.. (Taketa, K., Ichikawa, E., Taga, H., Hirai, H., Electrophoresis 1985, 6, 492-497) for AFP-P1-5. AFP-P2, the major AFP glycoform, was composed of AFP-I, AFP+I, and AFP+II; AFP-P3, a nonspecific monosialo-AFP, was composed of AFP+II; AFP-P4, HCC-specific monosialo-AFP, was composed of AFP+II, AFP+III, and AFP+IV; and malignancy-related AFP-P5 was composed of AFP+I and AFP+II. Monosialo-AFP (AFP+II) was recovered in all the glycoforms of AFP-P2, -P3, -P4, and -P5; thus, AFP-P4 is more specific to HCC than monosialylated AFP+II.

Carbohydrate Sequence↗
PubMed2006

Relationship between the proliferative capability of hepatocytes and the intrahepatic expression of hepatocyte growth factor and c-Met in the course of cirrhosis development in rats.

Liver cirrhosis is the fatal end stage of various chronic liver diseases. One of the most important causes of liver cirrhosis appears to be an impaired proliferative capability of hepatocytes caused by continuous hepatic damage. Hepatocyte growth factor (HGF) and its specific receptor, c-Met, play a pivotal role in hepatocyte proliferation. However, the relationship between the proliferative capability of hepatocytes and the intrahepatic expression of HGF and c-Met during the course of cirrhosis development has not been studied fully. In the present study, liver cirrhosis was produced in rats by intraperitoneally administering dimethylnitrosamine (DMN) and intrahepatic expression levels of HGF and c-Met were quantitatively estimated using a real-time reverse transcription-polymerase chain reaction (RT-PCR) method. Histological examination of liver sections and biochemical estimation of serum levels of transaminase revealed that the degree of hepatocyte destruction was elevated gradually during cirrhosis development in the DMN-induced rat cirrhosis model. The proliferative capability of hepatocytes estimated immunohistochemically by proliferating cell nuclear antigen staining was markedly increased at an early stage of cirrhosis development. However, it was gradually decreased thereafter and suppressed substantially at the time of cirrhosis manifestation. Intrahepatic HGF expression was also increased significantly during the course of cirrhosis development but decreased significantly at the time of cirrhosis manifestation. Conversely, there was a tendency for the intrahepatic expression of c-Met to decrease from an early stage of cirrhosis development and intrahepatic c-Met expression was decreased significantly at the time of cirrhosis manifestation. These results suggest that the highly proliferative capability of hepatocytes at an early stage of cirrhosis development is induced by increased intrahepatic HGF expression. However, both HGF and c-Met expression levels in the liver are decreased significantly there-after. Accordingly, the proliferative capability of hepatocytes is severely impaired and extracellular matrix components are deposited to retrieve space lost by the destruction of hepatic parenchyma, resulting in the establishment of liver cirrhosis.

Alanine Transaminase↗
PubMed2005

Estimation of the stent placement above the intact sphincter of Oddi against malignant bile duct obstruction.

BACKGROUND: In endoscopic biliary stenting against malignant biliary obstruction, stent blockage remains as an important problem. Stent blockage occurs as a result of bacterial adherence to the inner wall of the stent. We evaluated the stent placement above the intact sphincter of Oddi to retain the function of the sphincter of Oddi as a bacteriological barrier. METHODS: Sixteen patients with malignant biliary obstruction were assessed as the patients with the stent above the intact sphincter of Oddi. Sixteen patients with malignant biliary obstruction were assessed as the patients with the conventional stent placement across the sphincter of Oddi. Tannenbaum 10-Fr. stents were used in both the groups. RESULTS: The median patency periods of the stent were 255 days (25th to 75th percentiles, 212-454 days; range, 39-454 days) for the group of the stents placed above the sphincter of Oddi and 82 days (25th to 75th percentiles, 48-131 days; range, 22-196 days) for the group of the stents placed across the sphincter of Oddi, respectively, with significant difference (P = 0.0001). The occlusion rates of stents placed above and across the sphincter of Oddi were 37.5% and 93.8%, respectively, with significant difference (P = 0.0008). The dislocation rates of the stent were 0% and 6.3%, respectively (not significant). CONCLUSIONS: Placement of the stent above the intact sphincter of Oddi was associated with longer stent patency and lower occlusion rate.

Aged↗
PubMed2005

Adenocarcinoma arising from aberrant pancreas in the stomach.

We report herein a rare case of malignant transformation of aberrant pancreas in the stomach, associated with gastric outlet obstruction. A 58-year-old woman was admitted to our hospital, complaining of vomiting. Although barium meal examination and gastric endoscopy showed marked pyloric stenosis, the biopsy specimen obtained from the stenotic site revealed regenerative mucosa without malignancy. Abdominal computed tomography and endoscopic ultrasonography (EUS) also could not detect the cause of the obstruction. Histopathological examination of the surgically resected specimen showed the malignant transformation of aberrant pancreas in the stomach. It should be noted that one of the causes of gastric outlet obstruction may be aberrant pancreas or its malignant transformation.

Adenocarcinoma↗
PubMed2005

Pre-cutting using a noseless papillotome with independent lumens for contrast material and guidewire.

BACKGROUND: The technical success of therapeutic endoscopic retrograde cholangiopancreatography (ERCP) depends on selective cannulation into the bile duct. We have developed a new type of precut papillotome for selective cannulation. METHODS: The newly developed precut papillotome has been equipped not only with a lumen for contrast materials but also with an independent lumen for the guidewire. The operation of the guidewire and the injection of contrast material can be carried out simultaneously. The precut papillotome has a 20-mm-long knife and no leading tip. Half the proximal side of the knife is coated for insulation. RESULTS: Selective biliary cannulation failed in 26 of 293 patients (8.9%) in whom therapeutic ERCP was attempted. We applied the precut papillotome to these 26 patients and selective cannulation was successful in 24 of 26 patients (success rate: 92.3%). No major complications occurred, although mild bleeding, which did not require endoscopic hemostasis or blood transfusion, was observed only in one patient. CONCLUSIONS: Although further studies with a large number of patients are needed to evaluate the efficacy of the papillotome, this papillotome may contribute to increase the safety and the success rate of precutting.

Aged↗
PubMed2005

Adenovirus-mediated gene transfer into rat livers: comparative study of retrograde intrabiliary and antegrade intraportal administration.

To examine the feasibility of liver-directed in vivo gene therapy, we administered recombinant adenoviruses carrying a reporter lacZ gene retrogradely into the common bile duct of rats, as well as antegradely into the portal vein. Transduction efficiency of the lacZ gene in the liver was estimated not only histochemically by X-gal staining, but also quantitatively by a chemiluminescent reporter gene assay. Retrograde infusion of adenoviruses into the common bile duct was shown to successfully induce transgene expression in the liver. Transduction efficiency induced by intrabiliary adenoviral administration was not significantly different from that induced by intraportal adenoviral administration. Although transgene expression induced not only by intraportal, but also by intrabiliary adenoviral administration was observed predominantly at periportal areas, a considerable number of cells expressing the transgene were detectable even in lobular and centrilobular areas. Mild infiltration of inflammatory cells into the liver and mild hyperplastic changes of hepatocytes were observed after intrabiliary and intraportal adenoviral administration. However, hepatic damage estimated pathologically was not substantial. Furthermore, although intrabiliary and intraportal adenoviral administration resulted in very mild elevation of liver-related serum biochemical parameters, apparent complications were not observed in any rats. Our results demonstrated in the present study suggest that retrograde administration of adenoviruses into the common bile duct can induce efficient transgene expression in the liver without causing severe adverse effects, supporting the feasibility of adenovirus-mediated gene transfer into the liver in clinical settings by means of endoscopic retrograde cholangiography.

Adenoviridae↗
PubMed2005

Comparison study of the expressions of myristoylated alanine-rich C kinase substrate in hepatocellular carcinoma, liver cirrhosis, chronic hepatitis, and normal liver.

The myristoylated alanine-rich C kinase substrate (MARCKS) is a prominent substrate for protein kinase C (PKC) in a variety of cells. The aim of this study was not only to evaluate the expression and localization of MARCKS in various pathological liver tissues, including HCC, but also to analyze the difference in MARCKS expression between hepatitis virus-induced HCC and cirrhosis. The level of MARCKS and its phosphorylated proteins, as well as its localization, were determined using Western blot and/or immunohistochemistry in HCC and other pathological liver tissues. We also analyzed the change of MARCKS localization on the influence of MARCKS phosphorylation in the HLF cancer cell line by phosphorylation study. In addition, the relationship between MARCKS expression and proliferative activity was studied in HCC. In the immunohistochemical study, a very small amount of MARCKS protein was found along the contour of the hepatocellular membrane in normal liver and in cases of chronic hepatitis. MARCKS was up-regulated in liver cirrhosis tissue and was localized in the cytoplasm of hepatocytes. The expression of MARCKS was down-regulated in HCC tissues, as compared with non-tumorous liver cirrhosis tissues from the same patients. Furthermore, MARCKS was serine-phosphorylated in liver cirrhosis and HCC, and phosphorylated MARCKS was detected in a cytosolic fraction of these tissues. In a phosphorylation study using the HLF HCC cell line, MARCKS was displaced from the plasma membrane to the cytosol following the activation of protein kinase C (PKC) by phorbol 12-myristrate 13-acetate (PMA). Furthermore, the activity of cyclin D1 and cyclin E kinases was found to be higher in HCCs with low MARCKS expression than in HCCs with high MARCKS expression. These results suggest that up-regulation of MARCKS might be essential in the generation of cirrhotic nodules through chronic hepatitis from normal liver, and that the phosphorylation and/or down-regulation of MARCKS might play an important role in the development and progression of HCC from liver cirrhosis.

Adult↗
PubMed2005

Antitumor effects of vitamins K1, K2 and K3 on hepatocellular carcinoma in vitro and in vivo.

A number of studies have shown that various K vitamins, specifically vitamins K2 and K3, possess antitumor activity on various types of rodent- and human-derived neoplastic cell lines. In the present study, we examined the antitumor effects of vitamins K1, K2 and K3 on PLC/PRF/5 human hepatocellular carcinoma (HCC) cells in vitro and in vivo. Furthermore, we examined the mechanisms of antitumor actions of these vitamins in vitro and in vivo. Although vitamin K1 did not inhibit proliferation of PLC/PRF/5 cells at a 90-microM concentration (the highest tested), vitamins K2 and K3 suppressed proliferation of the cells at concentrations of 90 and 9 microM, respectively. By flow cytometric analysis, it was shown that not only vitamin K1, but also vitamin K2 did not induce apoptosis or cell cycle arrest on PLC/PRF/5 cells. In contrast, vitamin K3 induced G1 arrest, but not apoptosis on PLC/PRF/5 cells. Subsequent in vivo study using subcutaneous HCC-bearing athymic nude mice demonstrated that both vitamins K2 and K3 markedly suppressed the growth of HCC tumors to similar extent. Protein expression of cyclin D1 and cyclin-dependent kinase 4 (Cdk4), but not p16INK4a Cdk inhibitor in the tumor was significantly reduced by vitamin K2 or K3 treatment, indicating that vitamins K2 and K3 may induce G1 arrest of cell cycle on PLC/PRF/5 cells in vivo. Taken collectively, vitamins K2 and K3 were able to induce potent antitumor effects on HCC in vitro and in vivo, at least in part, by inducing G1 arrest of the cell cycle. The results indicate that vitamins K2 and K3 may be useful agents for the treatment of patients with HCC.

Animals↗
PubMed2005

Enhanced expression of p46 Shc in the nucleus and p52 Shc in the cytoplasm of human gastric cancer.

Shc protein is known to be related to cell proliferation and carcinogenesis. However, the involvement of Shc in gastric cancer remains unknown. In the present study, we examined the expression and localization of Shc in human gastric cancer and the adjacent normal mucosa by Western blotting and immunohistochemical analyses. Furthermore, the expression of Shc in a gastric cancer cell line, MKN 28, was also studied. p66 Shc was not detected at all in gastric cancer or the adjacent normal mucosa. In contrast, immunohistochemical and Western blot analyses revealed that p52 Shc was detected in the cytoplasmic fractions obtained from gastric normal mucosa and cancer, while p46 Shc expression was observed in the nuclear fractions from gastric normal mucosa and cancer. Furthermore, not only p52 Shc expression in the cytoplasm but also p46 Shc expression in the nucleus was much higher in gastric cancer than in the adjacent normal mucosa. Subsequent in vitro experiments with MKN 28 gastric cancer cells also revealed that p52 Shc was expressed solely in the cytoplasm and p46 Shc was solely in the nucleus. These results suggest that the enhancement of p46 Shc and p52 Shc expression may be related to the occurrence of gastric cancer. Furthermore, unlike p52 Shc, p46 Shc was shown to be expressed solely in the nucleus, suggesting that p46 Shc expressed in the nucleus may play an important role in gastric carcinogenesis.

Adaptor Proteins, Signal Transducing↗
PubMed2005

In vitro and in vivo antitumor effects of vitamin K5 on hepatocellular carcinoma.

Although a number of studies have shown that vitamins K1, K2 and K3 exerted antitumor effects on various types of rodent- and human-derived neoplastic cell lines, it has not been examined whether or not vitamin K5 also possesses antitumor activity. In the present study, we examined the antitumor effects of vitamin K5 on PLC/PRF/5 human hepatocellular carcinoma (HCC) cells in vitro and in vivo. Furthermore, we examined the mechanisms of antitumor actions of vitamin K5 not only in vitro but also in vivo. Vitamin K5 was shown to suppress the proliferation of PLC/PRF/5 cells at a concentration of 30 microM. By a flow cytometric analysis, it was shown that although vitamin K5 did not induce apoptosis on PLC/PRF/5 cells, it did induce G1 arrest on PLC/PRF/5 cells. Subsequent in vivo study using subcutaneous HCC-bearing athymic nude mice demonstrated that vitamin K5 markedly suppressed the growth of HCC tumors. Although protein expression levels of cyclin D1 and p16INK4a cyclin-dependent kinase (Cdk) inhibitor in HCC tumors were not decreased by vitamin K5 treatment, those of Cdk4 were reduced significantly by the treatment. Taken collectively, vitamin K5 could induce potent antitumor effects on HCC not only in vitro but also in vivo, at least in part by inducing G1 arrest of cell cycle through downregulation of Cdk4 expression. The results demonstrated here indicate that vitamin K5 may be a useful agent for the treatment of patients with HCC.

Animals↗
PubMed2005

Safe and efficient transgene expression in rat hepatocytes induced by adenoviral administration into the biliary tract.

We examined whether retrograde intrabiliary adenoviral administration could induce safe and efficient transgene expression in hepatocytes. We administered recombinant adenovirus carrying a reporter lacZ gene retrogradely into the common bile duct of rats and evaluated the transduction efficiency of the lacZ gene in the liver histochemically by X-gal staining, and also quantitatively by a chemiluminescent reporter gene assay. Retrograde administration of adenovirus into the common bile duct was shown to successfully induce transgene expression in the liver. Although transgene expression induced by intrabiliary adenoviral administration was observed predominantly at periportal areas, a considerable number of cells expressing the transgene were detectable even in lobular and centrilobular areas. Furthermore, histochemical analysis revealed that intrabiliary adenoviral administration resulted in gene transfer into hepatocytes, but not into biliary epithelial cells. Transgene expression in the liver was transient, and pathological and biochemical analyses revealed that hepatic damage caused by intrabiliary adenoviral administration was not substantial. The results demonstrated in the present study suggest that retrograde administration of adenovirus into the common bile duct can induce safe and efficient transgene expression in hepatocytes without causing considerable adverse effects, supporting the feasibility of adenovirus-mediated gene transfer into hepatocytes in clinical settings by means of endoscopic retrograde cholangiography.

Adenoviridae↗
PubMed2005

Vitamins K2, K3 and K5 exert in vivo antitumor effects on hepatocellular carcinoma by regulating the expression of G1 phase-related cell cycle molecules.

A number of studies have shown that various vitamins K, specifically vitamin K2, possessed antitumor activity on various types of rodent- and human-derived neoplastic cell lines. However, there are only a small number of reports demonstrating in vivo antitumor effects of vitamins K. Furthermore, the mechanism of antitumor effects of vitamins K still remains to be examined. In the present study, we examined the antitumor effects of vitamins K2, K3 and K5 on PLC/PRF/5 human hepatocellular carcinoma (HCC) cells in vivo. Furthermore, to examine the mechanism of antitumor actions of these vitamins K, mRNA expression levels of various G1 phase-related cell cycle molecules were evaluated by using a real-time reverse transcription-polymerase chain reaction (RT-PCR) method. HCC-bearing animals were produced by implanting PLC/PRF/5 cells subcutaneously into athymic nude mice, and drinking water containing vitamin K2, K3 or K5 was given to the animals. Treatments with vitamins K2, K3 and K5 were shown to markedly inhibit the growth of HCC tumors. To examine the mechanism of in vivo antitumor effects of vitamins K, total RNA was extracted from HCC tumors, and the expression of G1 phase-related cell cycle molecules was quantitatively examined. Real-time RT-PCR demonstrated that the expression of the cell cycle-driving molecule, cyclin-dependent kinase 4 (Cdk4), in HCC was significantly reduced by the treatments with vitamin K2, K3 and K5. Conversely, the expression of the cell cycle-suppressing molecules, Cdk inhibitor p16INK4a and retinoblastoma, in HCC was significantly enhanced by the treatments with vitamins K2, K3 and K5. These results indicate that vitamins K2, K3 and K5 exert antitumor effects on HCC by regulating the expression of G1 phase-related cell cycle molecules. These results also indicate that vitamins K2, K3 and K5 may be useful agents for the treatment of patients with HCC.

Alanine Transaminase↗
PubMed2005

Analyses of autoantibodies against tumor-associated antigens in patients with hepatocellular carcinoma.

Autoantibodies against tumor-associated antigens (TAAs) such as insulin-like growth factor II mRNA-binding proteins (IMPs), p53, c-myc, and survivin were analyzed in patients with hepatocellular carcinoma (HCC), using recombinant proteins of these antigens. Eight of 86 (9.3%) HCC patients had one or more of these autoantibodies. However, serum alpha-fetoprotein (AFP) levels ranged within normal limits in HCC patients with anti-TAAs except for one case with anti-IMP1. One of the HCC patients had autoantibodies against IMP1, IMP3 and p53 before the diagnosis of HCC. These findings may indicate that anti-TAAs seem to be supplementary serological markers for the diagnosis of HCC in AFP-negative cases and that autoantibodies against IMP1, IMP3 and p53 are candidates for predictive markers of HCC development.

Antigens, Neoplasm↗
PubMed2005

Repetitive and safe transgene expression in rat liver is achievable by adenoviral infusion into the common bile duct.

To examine the feasibility of adenovirus-mediated gene transfer into the liver, we examined whether adenoviral infusion into the common bile duct could induce repetitive and safe transgene expression in rat livers. Recombinant adenovirus carrying a reporter lacZ gene was repetitively infused retrogradely into the common bile duct of rats. LacZ expression in rat livers was estimated histochemically by X-gal staining and quantitatively by a chemiluminescent reporter gene assay after the first, second and third adenoviral infusion into the common bile duct. To assess the safety of repetitive adenoviral infusion into the common bile duct, various liver- and kidney-related serum parameters, and liver damage were examined biochemically and histologically, respectively. Retrograde adenoviral infusion into the common bile duct achieved sufficient and safe lacZ expression in rat livers. Although transgene expression in the liver was transient, the second and third adenoviral infusion into the common bile duct could induce the expression of the same transgene in the liver. Furthermore, repetitive adenoviral infusion into the common bile duct caused no significant reverse reactions. Because retrograde adenoviral infusion into the common bile duct is a clinically practical method by using a widely used endoscopic technique, namely endoscopic retrograde cholangiography, these results suggest that retrograde adenoviral infusion into the common bile duct is a practical gene therapy modality in clinical settings.

Adenoviridae↗
PubMed2004

Reduced expression of cell cycle regulator p18(INK4C) in human hepatocellular carcinoma.

Cyclins, cyclin-dependent kinases (Cdks), and Cdk inhibitors (CdkIs) are frequently altered in human cancer. p18INK4C, a member of the INK4 family of CdkIs, is a potential tumor-suppressor gene product. However, the expression of p18INK4C in hepatocellular carcinoma (HCC) remains unknown. The aim of this study was to examine the expression of p18INK4C in various liver diseases including HCC and to assess its clinical significance in HCC. To that end, we examined the expression of p18INK4C by immunohistochemistry in various liver diseases, including 51 HCCs, and also studied the relationship between p18INK4C expression, the phosphorylation of retinoblastoma protein (pRb), and the activity level of Cdk4 and Cdk6. Immunohistochemical analysis revealed the frequent loss of p18INK4C expression in HCC, especially in poorly differentiated HCC. The loss of p18INK4C expression was shown to be associated with a poor prognosis compared with that associated with p18INK4C- positivity. Further, the kinase activity of Cdk4 was found to be higher in p18INK4C-negative HCCs than in p18INK4C- positive HCCs. However, the level of Cdk6 activity was similar in the 2 groups of HCCs. In p18INK4C- positive HCCs, p18INK4C dominantly interacted with Cdk4 rather than with Cdk6. pRb phosphorylated at serine(Ser) 780 was detected more frequently in p18INK4C - negative than in p18INK4C - positive HCCs. In conclusion, the loss of p18INK4C expression may play a role in the differentiation and development of HCC through the up-regulation of Cdk4 activity.

Adult↗