Biomedical subjects

Siu Tim Cheung

Publications and source records attributed to Siu Tim Cheung.

14 recordsLinked to original sources

PubMed2007

Atypical localization of membrane type 1-matrix metalloproteinase in the nucleus is associated with aggressive features of hepatocellular carcinoma.

Membrane type 1-matrix metalloproteinase (MT1-MMP) is a versatile proteinase and recent studies indicated it could be internalized. Our earlier study found that it is overexpressed in hepatocellular carcinoma (HCC) and could promote intrahepatic metastasis. The present study was conducted to examine its subcellular localization and its clinicopathological significance in HCC after curative partial hepatectomy. Localization of MT1-MMP in 101 pairs of HCCs and their adjacent liver tissues, and 8 normal liver tissues was examined by the immunohistochemical method. MT1-MMP protein was localized at membrane and cytoplasm of hepatocytes in the normal and tumor adjacent liver tissues. In contrast, the HCCs were highly heterogeneous with variable degrees of membrane, cytoplasmic, and even nuclear staining. Interestingly, patients with presence of nuclear MT1-MMP were associated with poor overall survival (log-rank test, P=0.043) and large tumor size (>5 cm) (Fisher's exact test, P=0.031). Subcellular distribution was further demonstrated by Western blotting and immunofluorescence with Hep3B stable transfectant overexpressing MT1-MMP. Western blot analyses of subcellular fractions confirmed a differential partitioning of various post-translationally modified MT1-MMP in these fractions. Different antibodies corroborated the presence of MT1-MMP in the nuclear fraction. Concomitant nuclear presence of MMP2 with MT1-MMP further indicated its potential involvement in the nuclear functions. MT1-MMP co-localized with caveolin-1 at the perinuclear region, suggesting nuclear translocation of MT1-MMP via caveolae-mediated endocytosis. In summary, the association of nuclear MT1-MMP with aggressive tumor features including poor prognosis and large tumor expands its functional repertoire and further indicates a new functional role of MMPs within nuclei of tumor cells.

Adolescent↗

PubMed2006

Increased expression of glycosyl-phosphatidylinositol anchor attachment protein 1 (GPAA1) is associated with gene amplification in hepatocellular carcinoma.

Glycosyl-phosphatidylinositol (GPI) anchor attachment protein 1 (GPAA1) transcript level was frequently up-regulated in our earlier study on gene expression profile. We therefore analyzed the potential involvement of GPAA1 in hepatocellular carcinoma (HCC) as GPAA1 gene locates at chromosome 8q24.3 which chromosome region is frequently amplified in HCCs. In this study, we observed that GPAA1 transcript in the HCCs (n = 93) showed a significantly higher expression level compared with their paralleled adjacent nontumor liver tissues, cirrhosis (n = 15) and normal (n = 16) liver tissues using real-time quantitative RT-PCR (p < 0.005). We also demonstrated that GPAA1 protein up-regulation was common in HCCs (90%, 9/10), and GPAA1 gene was frequently amplified (73%, 11/15) using quantitative microsatellite analysis. Increased GPAA1 expression was significantly associated with HCCs poor cellular differentiation (p = 0.011) and poor prognosis (p = 0.010). We then modulated the GPAA1 expression level in HCC cells (Hep3B) by transfection experiments, which was shown to positively regulate cell adhesion ability (p = 0.004) and proliferation rate (p = 0.037). Our data revealed GPAA1 gene amplification with overexpression of RNA and protein in HCC. GPAA1 is a potential amplification target of chromosome 8q and responsible to regulate tumor cells behavior.

Aged↗

PubMed2006

Liver intestine-cadherin (CDH17) haplotype is associated with increased risk of hepatocellular carcinoma.

PURPOSE: Hepatocellular carcinoma (HCC), the most common form of liver cancer, is a leading cause of cancer death worldwide. We previously showed that aberrant mRNA splicing of the liver intestine-cadherin gene CDH17 in liver tissues was triggered by the specific constellation of two CDH17 single nucleotide polymorphisms (651T and IVS6+35G). CDH17 aberrant splicing was highly associated with tumor dissemination and shorter survival of HCC patients. Consequently, it is highly relevant to assess whether the presence of these single nucleotide polymorphisms in the general population represents a risk to the development of HCC. EXPERIMENTAL DESIGN: We conducted a case-control study including 164 HCC and 99 cirrhosis patients and 293 healthy controls. Genotyping was done by PCR and direct sequencing. Odds ratio (OR) and chi2 analysis were used to analyze genotypes and haplotypes. RESULTS: Genotypes 651TT [OR, 2.62; 95% confidence interval (95% CI), 1.34-5.03] and IVS6+35 GG (OR, 1.95; 95% CI, 1.04-3.62) were highly associated with HCC disease. The 651T (C>T) and IVS6+35G (A>G) alleles were also overrepresented in HCC patients and, in particular, the T-G haplotype was the most prevalent in HCC patients when compared with healthy controls (OR, 1.57; 95% CI, 1.167-2.109; P=0.004), which was in agreement with the aberrant splicing observed in tumor tissues. There was no significant difference in genotype and allele frequencies between cirrhosis patients and controls. CONCLUSION: The functional T-G haplotype of CDH17 (651 C>T and IVS6+35A>G) is a genetic susceptibility factor for the development of HCC in a Chinese population.

Alleles↗

PubMed2006

Anterior approach versus conventional approach right hepatic resection for large hepatocellular carcinoma: a prospective randomized controlled study.

OBJECTIVE: To evaluate whether major right hepatectomy using the anterior approach technique for large hepatocellular carcinoma (HCC) results in better operative and long-term survival outcomes when compared with the conventional approach technique. SUMMARY BACKGROUND DATA: The anterior approach technique has been advocated recently for large right liver tumors. However, its beneficial effects on the operative and survival outcomes of the patients have not been evaluated prospectively. METHODS: A prospective randomized controlled study was performed on 120 patients who had large (> or =5 cm) right liver HCC and underwent curative major right hepatic resection during a 57-month period. The patients were randomized to undergo resection of the tumor using the anterior approach technique (AA group, n = 60) or the conventional approach technique (CA group, n = 60). The anterior approach technique involved initial vascular inflow control, completion of parenchymal transection, and complete venous outflow control before the right liver was mobilized. Operative and long-term survival outcomes of the two groups were analyzed. Quantitative assessments of markers of circulating tumor cells at various stages of surgery of the two techniques were also assessed by plasma albumin-mRNA. RESULTS: The overall operative blood loss, morbidity, and duration of hospital stay were comparable in both groups. Major operative blood loss of > or =2 L occurred less frequently in the AA group (8.3% vs. 28.3%, P = 0.005). As a result, blood transfusion requirement and number of patients requiring blood transfusion were significantly lower in the AA group. Hospital mortality occurred in 1 patient in the AA group and 6 patients in the CA group (P = 0.114). Median disease-free survival was 15.5 months in the AA group and 13.9 months in the CA group (P = 0.882). Overall survival was significantly better in the AA group (median >68.1 months) than in the CA group (median = 22.6 months, P = 0.006). The survival benefit appeared more obvious in patients with stage II disease and patients with lymphovascular permeation of the tumor. The anterior approach was also found to associate with significantly lower plasma albumin-mRNA levels at various stages of surgery compared with the CA technique. On multivariate analysis, tumor staging, anterior approach hepatic resection, and resection margin involved by the tumor were independent factors affecting overall survival. CONCLUSION: The anterior approach results in better operative and survival outcomes compared with the conventional approach. It is the preferred technique for major right hepatic resection for large HCC.

Blood Loss, Surgical↗

PubMed2006

Preoperative plasma transcript AA454543 level is an independent prognostic factor for hepatocellular carcinoma after partial hepatectomy.

BACKGROUND: We have previously reported that tissue expression levels of transcript AA454543 in hepatocellular carcinoma (HCC) are significantly higher than those of normal livers, livers with cirrhosis, and livers with hepatitis. In addition, a higher level of transcript AA454543 in tumor tissues is associated with poor prognosis. We aim to examine whether quantitative measurement of preoperative plasma transcript AA454543 can provide similar prognostic information. PATIENTS AND METHODS: Blood samples were obtained from 84 HCC patients before surgery. Real-time quantitative reverse transcription-polymerase chain reaction, using TaqMan system, was employed to measure plasma transcript AA454543 and alpha-fetoprotein (AFP) RNA levels. We assessed their prediction power in prognosis using univariate and multivariate analyses. RESULTS: High plasma transcript AA454543 RNA levels were associated with poor overall survival (log-rank test, P < .01). Patients with different plasma AFP RNA levels revealed no difference in overall survival (log-rank test, P = .88). By multivariate Cox regression analysis, plasma transcript AA454543 RNA level (hazard ratio = 4.8, P < .01) and tumor stage (hazard ratio = 1.7, P < .01) were determined to be independent risk factors for the prediction of overall survival. CONCLUSION: Preoperative plasma transcript AA454543 RNA level can provide prognostic information for HCC patients receiving curative partial hepatectomy.

Adult↗

PubMed2006

GEP associates with wild-type p53 in hepatocellular carcinoma.

Granulin-epithelin precursor (GEP) is a novel growth factor whose up-regulation we previously reported in 72% of hepatocellular carcinoma (HCC). GEP expression has been reported to be associated with p53 protein accumulation in a breast cancer study, though the p53 mutation status was not revealed. We aim to investigate whether p53 protein and mutation status correlates with GEP expression in HCC. The statistical comparison of p53 and GEP data revealed an overall positive association between the two protein expression patterns (P<0.001). Upon detailed analysis, the association of p53 and GEP protein expression was found to be highly significant only in HCCs with wild-type p53 (P=0.001); there was no association in HCCs with p53 mutation (P=0.669). The GEP levels in the HepG2 hepatoma cell line with a wild-type p53 background were modulated by transfection experiments. Overexpression of the GEP protein resulted in an increased p53 protein level and suppression of the GEP protein resulted in a decreased p53 protein level in HepG2 cells. In summary, we demonstrated that p53 wild-type protein nuclei accumulation is associated with GEP protein expression in human HCC specimens, and GEP modulates p53 wild-type protein levels in vitro.

Carcinoma, Hepatocellular↗

PubMed2005

Claudin-10 expression level is associated with recurrence of primary hepatocellular carcinoma.

PURPOSE: Hepatocellular carcinoma (HCC) patients with the same clinicopathologic features can have remarkably different disease outcomes after curative hepatectomy. To address this issue, we evaluated the cDNA microarray gene expression profiles of HCCs and identified claudin-10 expression level was associated with disease recurrence. The aim of the current study is to validate the microarray data by an alternative research method applicable for routine practice. EXPERIMENTAL DESIGN: Quantitative reverse transcription-PCR (RT-PCR) was used to validate the microarray data on claudin-10 expression level. The assay was repeated on a separate HCC sample set to consolidate the prognostic significance of claudin-10. RESULTS: Claudin-10 expression level by quantitative RT-PCR and by microarray measurement showed a high concordance (r = 0.602, P < 0.001). Quantitative RT-PCR was repeated on a separate HCC sample set and the association of claudin-10 expression with recurrence was again confirmed (hazard ratio, 1.2; 95% confidence interval, 1.0-1.4; P = 0.011). By multivariable Cox regression analysis, claudin-10 expression and pathologic tumor-node-metastasis stage were independent factors for prediction of disease recurrence. CONCLUSION: Claudin-10 expression of HCC can be used as a molecular marker for disease recurrence after curative hepatectomy.

Carcinoma, Hepatocellular↗

PubMed2005

Transcript AA454543 is a novel prognostic marker for hepatocellular carcinoma after curative partial hepatectomy.

BACKGROUND: We have previously reported on the cDNA microarray gene expression profiles of hepatocellular carcinomas (HCCs). Among the genes that show prognostic significance and are overexpressed in tumor compared with adjacent nontumorous liver, transcript AA454543 may have potential for practical use. Our aim is to validate the prognostic significance of transcript AA454543 by alternative research methods and in a separate group of HCC patients. METHODS AND RESULTS: The data of transcript AA454543 derived from microarray analysis of 48 patients having curative partial hepatectomy (group 1) were verified by quantitative reverse transcription polymerase chain reaction (r = 0.618, P < .001). A separate sample set of HCCs obtained from 53 patients (group 2) was examined and the association of AA454543 expression level with overall survival was again validated (P = .027). By Cox regression analysis, transcript AA454543 [hazard ratio (HR) = 3.0, P = .017] and pathologic tumor node metastasis (pTNM) stage (HR = 3.3, P = .010) were independent prognostic factors for overall survival. The accuracy of prediction for 3-year overall survival for transcript AA454543 (74.2%, P = .001) and pTNM stage (76.4%, P = .001) was comparable as measured by the area under the receiver operating characteristic curve. CONCLUSION: Transcript AA454543 is potentially useful molecular prognostic marker for overall survival after curative partial hepatectomy for HCC.

Adolescent↗

PubMed2004

Granulin-epithelin precursor overexpression promotes growth and invasion of hepatocellular carcinoma.

PURPOSE: Granulin-epithelin precursor (GEP) is a novel growth factor. Our earlier cDNA microarray study indicated that GEP was overexpressed in hepatocellular carcinoma (HCC). The aim of this study was to investigate the clinical significance of GEP expression and its potential as a therapeutic target in HCC. EXPERIMENTAL DESIGN: A total of 110 pairs of HCCs and adjacent nontumor liver tissues, and 22 normal liver tissues were examined. The GEP RNA level was examined by quantitative reverse transcription-PCR, and protein localization by immunohistochemistry. The GEP function was examined by transfection experiments. RESULTS: The RNA levels of the HCCs were significantly higher than those of the nontumor liver tissues and normal livers (P <0.001). GEP protein staining was observed in tumor cytoplasm, and the GEP protein levels of the HCCs were also significantly higher than those of the nontumor liver tissues and normal livers (P <0.001). The majority of HCCs demonstrated up-regulation of GEP protein compared with their adjacent liver tissues [79 (71.8%) of 110]. Positive correlation of GEP RNA with protein levels was observed in HCCs (P <0.01). Strong GEP expression was associated with large HCCs, venous infiltration, and early intrahepatic recurrence (P <0.05). Functional studies on the HCC cell line Hep3B demonstrated that reduction of GEP protein levels resulted in decreased cell proliferation rates, tumor invasion ability, anchorage-independent growth in soft agar, and tumorigenicity in nude mice (P <0.05). CONCLUSION: GEP is an important factor for HCC growth, invasion, and metastasis. GEP has the potential to serve as a tumor marker and therapeutic target.

Animals↗

PubMed2004

Decreased expression of cytochrome P450 2E1 is associated with poor prognosis of hepatocellular carcinoma.

Cytochrome P450-2E1 (CYP2E1) is one of the major hepatic enzymes involved in the metabolism of procarcinogen. Our study aimed to investigate the differential expression level of CYP2E1 and its clinicopathological significance in hepatocellular carcinoma (HCC). CYP2E1 revealed low level of expression in 70% of the tumor tissues, when compared to the adjacent nontumor tissues, at both mRNA and protein levels. The low expression of CYP2E1 was significantly correlated with the aggressive tumor phenotype, including poor differentiation status (by the Edmondson grading system) (p=0.038), absence of tumor capsule (p=0.030) and younger age of the patients (p=0.002). Multivariate analysis indicated that CYP2E1 expression level and pTNM stage were independent prognostic factors for disease-free survival. CYP2E1 was also shown to have a differential expression level in different liver tissues. The level of CYP2E1 was significantly higher in nontumor tissues from HCC patients compared to the intermediate level in cirrhosis livers from noncancer patients and normal livers from healthy persons. Tumor tissues were shown to have the lowest expression level. In conclusion, our results have shown that CYP2E1 is upregulated in the nontumor tissue and downregulated in tumor tissue, which is associated with aggressive tumor type and poor prognosis of the patients. It suggested that the differential expression of CYP2E1 may play an important role in HCC tumorigenesis.

Adult↗

PubMed2004

Clinical significance of thrombospondin 1 expression in hepatocellular carcinoma.

PURPOSE: Thrombospondin 1 (THBS 1) is a matricellular protein capable of modulating angiogenesis. However, the actual role of THBS 1 in angiogenesis and tumor progression remains controversial. Hepatocellular carcinoma (HCC) is a hypervascular tumor characterized by neovascularization. The significance of THBS 1 in HCC remains unknown. In this study, the significance of THBS 1 in HCC was evaluated by correlating its expression with clinicopathological data. The possible role of THBS 1 in the angiogenesis of HCC was also studied by correlating its expression with vascular endothelial growth factor (VEGF) expression. EXPERIMENTAL DESIGN: Sixty HCC patients were recruited in this study. THBS 1 and VEGF protein expression in tumorous livers were localized by immunohistochemical staining and quantified by ELISA. THBS 1 mRNA was quantified by quantitative reverse transcription-PCR. RESULTS: Immunohistochemical staining of THBS 1 was positive in HCC cells in 51.7% of patients and in stromal cells in 65% of patients. Tumor THBS 1 protein level was significantly correlated with its mRNA expression (P = 0.001) and was significantly correlated with tumor VEGF protein levels (P = 0.001). Its expression was significantly associated with the presence of venous invasion (P = 0.008) and advanced tumor stage (P = 0.049). High THBS 1 expression was also a prognostic marker of poor survival in HCC patients. CONCLUSIONS: This study shows that high expression of THBS 1 is associated with tumor invasiveness and progression in HCC. THBS 1 appears to be a proangiogenic factor that stimulates angiogenesis in HCC in view of its positive correlation with VEGF expression.

Aged↗

PubMed2002

Identify metastasis-associated genes in hepatocellular carcinoma through clonality delineation for multinodular tumor.

Disease recurrence and metastasis are frequently observed in many successfullytreated localized cancers, including hepatocellular carcinoma in which intrahepatic and extrahepatic recurrence (metastasis) are frequently observed after curative resection. The present study aimed at identifying metastasis-associated genes through delineation of the clonality for multinodular liver cancer. The clonal relationship of 22 tumor foci from six patients was investigated by the genome-wide expression profile via cDNA microarray consisting of 23,000 genes. Tumor molecular properties including p53 protein overexpression and gene mutation, hepatitis B virus integration pattern, and genetic alteration examined by comparative genomic hybridization were compared. Results indicated that gene expression patterns could serve as the molecular fingerprint for clonality identification. Together with the molecular data from p53, hepatitis B virus integration and comparative genomic hybridization profiles, tumor nodules from five patients were confirmed with clonal relationship, and the expression profiles of the primary nodules were compared with their corresponding intrahepatic metastatic nodules. A total of 90 clones were found to be correlated with intrahepatic metastasis by Student's t test (P < 0.05). With reference to the primary tumor, 63 clones (39 known genes and 24 express sequence tags) were down-regulated whereas 27 clones (14 known genes and 13 express sequence tags) were up-regulated in the metastatic nodules. These metastasis-associated genes may provide clues to reveal patients with increased risk of developing metastasis, and to identify novel therapeutic targets for the treatment of metastasis.

Adolescent↗

PubMed2002

Liver as an ideal target for gene therapy: expression of CTLA4Ig by retroviral gene transfer.

BACKGROUND AND AIMS: Liver has been a target organ for gene therapy as it plays a central role in metabolism and production of serum proteins. Many metabolic disorders result from a deficiency of liver-derived protein products. In transplantation settings, modulation of the immune responses caused by CTLA4Ig protein has been shown to be an attractive direction. In this study, we investigated the efficacy of hepatocyte transduction via introduction of the exogenous CTLA4Ig gene to the rat liver graft by retrovirus vector, and examined the presence of target serum protein after gene transfers. METHODS: We constructed a replication defective retroviral vector that contained the CTLA4Ig gene. The liver graft regeneration index was first examined by 5-bromo-2-deoxyuridine, Ki-67 and proliferating cell nuclear antigen antibodies to determine the optimal time of gene transduction. The liver graft was then perfused with the retroviral vector, and animals were killed at constant time points to examine for the presence of CTLA4 protein in the graft and peripheral blood. RESULTS: CTLA4 protein was detected on postoperative days 5, 9 and 14, with liver graft tissue transduction indexes of 7.2, 10.9 and 1.8, respectively. Blood protein levels were at 151.6, 26.5 and 21.4 rhog/mL, respectively. A transduction index reaching 22.1 was observed in the graft with the most rapid liver regeneration. CONCLUSIONS: We had established the gene delivery model in rat with auxiliary partial liver transplantation. Expression of the exogenous gene delivered by retrovirus was demonstrated in the liver with secretion of diffusible protein in the bloodstream. The present study provides important information for gene transfer using the liver to produce the target protein in situ and as serum protein. This will also be applicable to the treatment of other metabolic diseases.

Abatacept↗

PubMed2002

Gene expression patterns in human liver cancers.

Hepatocellular carcinoma (HCC) is a leading cause of death worldwide. Using cDNA microarrays to characterize patterns of gene expression in HCC, we found consistent differences between the expression patterns in HCC compared with those seen in nontumor liver tissues. The expression patterns in HCC were also readily distinguished from those associated with tumors metastatic to liver. The global gene expression patterns intrinsic to each tumor were sufficiently distinctive that multiple tumor nodules from the same patient could usually be recognized and distinguished from all the others in the large sample set on the basis of their gene expression patterns alone. The distinctive gene expression patterns are characteristic of the tumors and not the patient; the expression programs seen in clonally independent tumor nodules in the same patient were no more similar than those in tumors from different patients. Moreover, clonally related tumor masses that showed distinct expression profiles were also distinguished by genotypic differences. Some features of the gene expression patterns were associated with specific phenotypic and genotypic characteristics of the tumors, including growth rate, vascular invasion, and p53 overexpression.

Carcinoma, Hepatocellular↗