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Deregulation of Wnt/β-catenin pathway is a hallmark of major gastrointestinal cancers including hepatocellular carcinoma (HCC). The oncogenic role of β-catenin is well defined but reasons for its accumulation in HCC remain unclear. Dickkopf 4 (DKK4) acts as a negative regulator of Wnt/β-catenin pathway but its functional role in liver carcinogenesis has not been studied. We investigated the role of DKK4 in β-catenin regulation in HCC. Reduced expression of DKK4 was found in 47% (38/81) of HCC, as measured by quantitative real time PCR. Ectopic expression of DKK4 in two HCC cell lines, PLC/PRF/5 (PLC) and MHCC97L (97L), attenuated β-catenin responsive luciferase activity, and decreased both β-catenin and cyclin D1 protein levels. To study the effect of DKK4 on cell growth and tumourigenicity, two stable HCC cell lines were established from PLC and 97L cells. Functional assays demonstrated that overexpression of DKK4 hampered cell proliferation, reduced colony formation and retarded cell migration. When DKK4-expressing 97L stable cells were used to induce tumour xenografts in nude mice (n=8), reduction in tumour sizes was observed (P=0.027). Furthermore, immunohistochemical studies showed that decreased expression of DKK4 was associated with β-catenin accumulation in HCC tissues. Additionally, inhibition of the proteasome using specific inhibitor in DKK4-expressing 97L stable cells masked the effect of β-catenin. Our findings suggest a potential tumour suppressive role of DKK4 as well as that of an important regulator of HCC.

The NF-kappaB signalling pathway plays important roles in liver organogenesis and carcinogenesis. Mouse embryos deficient in IKKbeta die in mid-gestation, due to excessive apoptosis of hepatoblasts. Although activation of the NF-kappaB signalling pathway has been demonstrated in human hepatocellular carcinoma, the role of NF-kappaB is controversial. Here, we have generated transgenic mice in which a constitutively active form of IKKbeta was expressed in a hepatocyte-specific manner. Using electrophoretic mobility shift assay, we documented increased NF-kappaB activities and up-regulated levels of NF-kappaB downstream target genes, Bcl-xL and STAT5, in the transgenic mouse livers. These results confirmed that the NF-kappaB pathway was activated in the livers of the transgenic mice. However, there was no significant difference in tumour formation between transgenic and wild-type mice up to an age of 50 weeks. When we treated the transgenic mice with the chemical carcinogen diethylnitrosamine (DEN), we observed no significant differences in the incidence and size of liver tumours formed in these mice with and without DEN treatment at 35 weeks of age, suggesting that the activated NF-kappaB pathway in the livers of the transgenic mice did not enhance hepatocarcinogenesis. Interestingly, some of the transient transgenic embryos (E12.5) had abnormal excessive accumulation of nucleated red blood cells in their developing livers. In summary, NF-kappaB activation in hepatocytes did not significantly affect chemical hepatocarcinogenesis. In addition, the TTR/IKKCA transgenic mice may serve as a useful model for studying the role of NF-kappaB activation in hepatocarcinogenesis as well as inflammatory and metabolic diseases.

Background: Hypothetical studies that favour living donor liver transplantation (LDLT) for early hepatocellular carcinoma (HCC) assumed a comparable outcome after LDLT and deceased donor liver transplantation (DDLT). The aim of this study was to compare the outcome after LDLT with that after DDLT, and to identify factors that might account for any differences., Methods: The study included 60 patients who met the radiological Milan or University of California at San Francisco (UCSF) criteria and underwent LDLT (43 patients) or DDLT (17)., Results: The LDLT group had fewer incidental tumours and a lower rate of pretransplant transarterial chemoembolization but a higher rate of salvage transplantation. Waiting time was shorter and graft weight to standard liver weight (GW : SLW) ratio was lower in this group. The perioperative course, and histopathological tumour size, number, grade and stage were comparable. Median follow-up was 33 (range 4-120) months. The cumulative 5-year recurrence rate was 29 per cent in the LDLT group and 0 per cent in the DDLT group (P = 0.029). A GW : SLW ratio of 0.6 or less, salvage transplantation, three or more tumour nodules, microscopic vascular invasion, and pathological stage beyond the Milan or UCSF criteria were significant confounding risk factors. Multivariable analysis identified salvage transplantation (relative risk 5.16 (95 per cent confidence interval (c.i.) 1.48 to 18.02); P = 0.010) and pathological stage beyond the UCSF criteria (relative risk 4.10 (95 per cent c.i. 1.02 to 16.48); P = 0.047) as independent predictors of recurrence., Conclusion: Despite standard radiological selection criteria based on number and size, patients who underwent LDLT for HCC had more recurrence because of selection bias for other clinical characteristics., (Copyright 2006 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

Background: Vascular endothelial growth factor (VEGF) and endostatin stimulate and inhibit tumour angiogenesis respectively. Recent studies have demonstrated the prognostic value of serum levels of both VEGF and endostatin in patients with various types of cancer. Their significance in patients with hepatocellular carcinoma (HCC) remains unclear., Methods: Serum VEGF and endostatin levels were measured by enzyme immunoassay in 108 patients with HCC before surgical resection and in 20 healthy controls. Preoperative serum VEGF and endostatin levels were correlated with clinicopathological features and long-term survival., Results: Serum VEGF levels in patients with HCC were significantly higher than those in controls, but serum levels of endostatin were similar in the two groups. High serum levels of VEGF, but not endostatin, were significantly associated with venous invasion and advanced tumour stage. Patients with a serum VEGF level higher than median (over 245.0 pg/ml) had significantly worse overall and disease-free survival than those with a lower level (P = 0.012 and P = 0.022 respectively). On multivariate analysis, serum VEGF level was an independent prognostic factor (hazard ratio 1.86 (95 per cent confidence interval 1.10 to 3.92); P = 0.032). Serum endostatin levels did not have significant prognostic influence on overall or disease-free survival., Conclusion: A high serum level of VEGF is a predictor of poor outcome after resection of HCC. Serum VEGF, but not endostatin, may be a useful prognostic marker in patients with HCC., (Copyright (c) 2004 British Journal of Surgery Society Ltd)

Aim: To compare the clinico-pathological features of hepatitis B virus-related hepatocellular carcinoma in young and old patients., Methods: The clinico-pathological characteristics of hepatitis B virus-related hepatocellular carcinoma were compared in 1863 consecutive patients (121 patients, 40 years) seen at a single institution over the last 13 years., Results: Young patients presented more often with pain (P < 0.0001), hepatomegaly (P = 0.01) and ruptured hepatocellular carcinoma (P = 0.02), whereas old patients presented with ankle oedema (P = 0.001), ascites (P = 0.002) and by routine screening (P = 0.035). Liver function, Child-Pugh grading and indocyanine green test were better preserved in young patients. They also had a higher alpha-foetoprotein concentration (P = 0.001), larger tumour size (P = 0.001) and more frequent metastasis (P = 0.008), but a similar surgical resection rate (33.6% vs. 28%), to old patients. There was no difference between the two groups in the overall post-resection survival rate, but there was a shorter survival in young patients with unresectable disease (3.6 months vs. 4.6 months, P = 0.004). Young patients with hepatocellular carcinoma often show a later presentation, but a higher resectability rate and similar survival rates, than old patients. The screening programme should include young hepatitis B virus carriers, even in the absence of cirrhosis.